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Clinical Neurophysiology

El Paso, TX. Chiropractor, Dr. Alexander Jimenez discusses clinical neurophysiology. Dr. Jimenez will explore the clinical significance and functional activities of peripheral nerve fibers, the spinal cord, brainstem, and brain in the context of visceral and musculoskeletal disorders. Patients will gain an advanced understanding of the anatomy, genetics, biochemistry, and physiology of pain in relation to various clinical syndromes. Nutritional biochemistry related to nociception and pain will be incorporated. And the implementation of this information into therapy programs will be emphasized.

Our team has takes great pride in bringing our families and injured patients only clinically proven treatments protocols.  By teaching complete holistic wellness as a lifestyle, we also change not only our patients lives but their families as well.  We do this so that we may reach as many El Pasoans who need us, no matter the affordability issues. For Answers to any questions you may have please call Dr. Jimenez at 915-850-0900.


Clinical Prediction Rules For Back And Spinal Pain Syndromes

Clinical Prediction Rules For Back And Spinal Pain Syndromes

Clinical Prediction Rules:

“Clinical decision rules, spinal pain classification and prediction of treatment outcome: A discussion of recent reports in the rehabilitation literature”

Abstract

Clinical decision rules are an increasingly common presence in the biomedical literature and represent one strategy of enhancing clinical-decision making with the goal of improving the efficiency and effectiveness of healthcare delivery. In the context of rehabilitation research, clinical decision rules have been predominantly aimed at classifying patients by predicting their treatment response to specific therapies. Traditionally, recommendations for developing clinical decision rules propose a multistep process (derivation, validation, impact analysis) using defined methodology. Research efforts aimed at developing a “diagnosis-based clinical decision rule” have departed from this convention. Recent publications in this line of research have used the modified terminology “diagnosis-based clinical decision guide.” Modifications to terminology and methodology surrounding clinical decision rules can make it more difficult for clinicians to recognize the level of evidence associated with a decision rule and understand how this evidence should be implemented to inform patient care. We provide a brief overview of clinical decision rule development in the context of the rehabilitation literature and two specific papers recently published in Chiropractic and Manual Therapies.

Clinical Prediction Rules

clinical prediction rules spine pain el paso tx.

  • Healthcare has undergone an important paradigm shift toward evidence based practice; an approach thought to enhance clinical decision making by integrating the best available evidence with clinical expertise and the preferences of patients.
  • Ultimately, the goal of evidence based practice is to improve healthcare delivery. However, the translation of scientific evidence into practice has proven a challenging endeavor.
  • Clinical decision rules (CDRs), also known as clinical prediction rules, are an increasingly common presence in the rehabilitation literature.
  • These are tools designed to inform clinical decision-making by identifying potential predictors of diagnostic test outcome, prognosis or therapeutic response.
  • In the rehabilitation literature, CDRs are most commonly used to predict a patient’s response to treatment and have been proposed as a means of identifying clinically relevant subgroups of patients presenting with otherwise heterogeneous disorders such as non-specific neck or low back pain and this is the perspective on which we intend to focus.

Clinical Prediction Rules

  • The ability to classify or subgroup patients with heterogeneous disorders such as spinal pain has been highlighted as a research priority and consequently, the focus of much research effort. The appeal of such classification approaches is their potential for improved treatment efficiency and effectiveness by matching patients with optimal therapies. In the past, patient classification has relied on implicit approaches founded in tradition or unsystematic observations. The use of CDRs to inform classification is one attempt at a more evidence driven approach, less dependent on unfounded theory.
  • CDRs are developed in a multistep process involving studies of derivation, validation and analysis of impact with each having a defined purpose and methodological criteria. As with all forms of evidence used to make decisions about patients, attention to appropriate study methodology is critical to assessing the potential benefits of implementation.

Benefits Of Clinical Prediction Rules

  • Can accommodate more factors than human brain can take into account
  • CDR/CPR model will always give the same result (mathematical equation)
  • Can be more accurate than clinical judgement.

Clinical Uses Of Clinical Prediction Rules

  • Diagnosis – Pretest probability
  • Prognosis – Predict risk of outcomes of disease

clinical prediction rules spine pain el paso tx.

 

clinical prediction rules spine pain el paso tx.

 

clinical prediction rules spine pain el paso tx.

https://johnsnyderdpt.com/for-clinicians/clinical-prediction-rules/cervical-manipulation-for-neck-pain/

clinical prediction rules spine pain el paso tx.

https://johnsnyderdpt.com/for-clinicians/clinical-prediction-rules/thoracic-manipulation-for-neck-pain/

clinical prediction rules spine pain el paso tx.

https://johnsnyderdpt.com/for-clinicians/clinical-prediction-rules/manipulation-for-low-back-pain

clinical prediction rules spine pain el paso tx.

https://johnsnyderdpt.com/for-clinicians/clinical-prediction-rules/lumbar-spinal-stenosis/

Dr. John Snyder’s Website

Flynn Clinical Prediction Rule Video

clinical prediction rules spine pain el paso tx.

CDR Analysis Of Impact

Ultimately, the usefulness of a CDR lies not with its accuracy but with its ability to improve clinical outcomes and enhance the efficiency of care.[15] Even when a CDR demonstrates evidence of broad validation, this does not ensure that it will change clinical decision making, or that the changes it produces will result in better care.

The changes it produces will result in better care. McGinn et al.[2] identified three explanations for the failure of a CDR at this stage. First, if clinician judgement is as accurate as a CDR informed decision, there is no benefit to its use. Second, the application of a CDR may involve cumbersome calculations or procedures which discourage clinicians from utilizing the CDR. Third, using the CDR may not be feasible in all environments or circumstances. In addition, we would include the reality that experimental studies may involve patients that are not entirely representative of those seen in routine care and that this may limit the actual value of a CDR. Therefore, to fully understand the utility of a CDR and its ability to improve healthcare delivery, it is necessary to undertake a pragmatic examination of its feasibility and impact when applied in an environment reflecting real world practice. This can be undertaken with different study designs such as randomized trials, cluster randomized trials, or other approaches such as examining the impact of a CDR before and after its implementation.

Prevalence of classification methods for patients with lumbar impairments using the McKenzie syndromes, pain pattern, manipulation, and stabilization clinical prediction rules.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3113271/

Objectives

Aims were (1) to determine the proportion of patients with lumbar impairments who could be classified at intake by McKenzie syndromes (McK) and pain pattern classification (PPCs) using Mechanical Diagnosis and Therapy (MDT) assessment methods, manipulation, and stabilization clinical prediction rules (CPRs) and (2) for each Man CPR or Stab CPR category, determine classification prevalence rates using McK and PPC.

CPRs are sophisticated probabilistic and prognostic models where a group of identified patient characteristics and clinical signs and symptoms are statistically associated with meaningful prediction of patient outcomes.
Two separate CPRs were developed by researchers for identifying patients who would respond favorably to manipulation.33,34 Flynn et al. developed the original manipulation CPR using five criteria, i.e. no symptoms below the knee, recent onset of symptoms (<16 days), low fear avoidance belief questionnaire36 score for work (<19), hypomobility of the lumbar spine, and hip internal rotation ROM (>35° for at least one hip).33
Flynn’s CPR was subsequently modified by Fritz et al. to two criteria, that included no symptoms below the knee and recent onset of symptoms (<16 days), as a pragmatic alternative to reduce clinician burden for identifying patients in primary care most likely to positively respond to thrust manipulation.34

“Potential Pitfalls Of Clinical Prediction Rules”

What Are Clinical Prediction Rules?

A clinical prediction rule (CPR) is a combination of clinical findings that have statistically demonstrated meaningful predictability in determining a selected condition or prognosis of a patient who has been provided with a specific treatment 1,2. CPRs are created using multi- variate statistical methods, are designed to examine the predictive ability of selected groupings of clinical variables3,4, and are intended to help clinicians make quick decisions that may normally be subject to underlying biases5. The rules are algorithmic in nature and involve condensed information that identifies the smallest number of indicators that are statistically diagnostic to the targeted condition6.

Clinical prediction rules are generally developed using a 3-step method14. First, CPRs are derived prospectively us-
ing multivariate statistical methods to examine the predictive ability of selected groupings of clinical variables3. The second step involves validating the CPR in a randomized controlled trial to reduce the risk that the predictive factors developed during the derivation phase were selected by chance14. The third step involves con- ducting an impact analysis to determine the extent that the CPR improves care, reduces costs, and accurately defines the targeted objective14.

Although there is little debate that carefully constructed CPRs can improve clinical practice, to my knowledge, there are no guidelines that specify methodological requirements for CPRs for infusion into all clinical practice environments. Guidelines are created to improve the rigor of study design and reporting. The following editorial outlines potential methodological pitfalls in CPRs that may significantly weaken the transferability of the algorithm. Within the field of rehabilitation, most CPRs have been prescriptive; thus, my comments here are reflective of prescriptive CPRs.

Methodological Pitfalls

CPRs are designed to specify a homogenous set of characteristics from a heterogeneous population of prospectively selected consecutive patients5,15. Typically, the resulting applicable population is a small subset of a larger sample and may only represent a small percentage of the clinician’s actual daily caseload. The set- ting and location of the larger sample should be generalizable15,16, and subsequent validity studies require assessment of the CPR in different patient groups, in different environments, and with a typical patient group seen by most clinicians16. Because many CPRs are developed based on a very distinct group, that may or may not be reflective of a typical population of patients, the spectrum transportability17 of many current CPR algorithms may be limited.

Clinical prediction rules use out- come measures to determine the effectiveness of the intervention. Outcome measures must have a single operational definition5 and require enough responsiveness to truly capture appropriate change in the condition14; in addition, these measures should have a well constructed cut-off score16,18 and be collected by a blinded administrator15. The selection of an appropriate anchor score for measurement of actual change is currently debated19-20. Most outcome measures use a patient recall-based questionnaire such as a global rating of change score (GRoC), which is appropriate when used in the short term but suffers from recall bias when used in long-term analyses19-21.

A potential drawback for CPRs is the failure to maintain the quality of the tests and measures used as predictors in the algorithm. The prospective test and measures should be independent of one another during modeling16; each should be performed in a meaningful, acceptable manner4; and clinicians or data administrators should be blinded to the patient’s outcomes measures and condition22.

Sources

Potential Pitfalls Of Clinical Prediction Rules; The Journal of Manual & Manipulative Therapy Volume 16 Number Two [69]

Jeffrey J Hebert and Julie M Fritz; Clinical decision rules, spinal pain classification and prediction of treatment outcome: A discussion of recent reports in the rehabilitation literature

The Role of Biomarkers for Depression

The Role of Biomarkers for Depression

Depression is one of the most common mental health issues in the United States. Current research suggests that depression results from a combination of genetic, biological, ecological, and psychological aspects. Depression is a major psychiatric disorder worldwide with a significant economic and psychological strain on society. Fortunately, depression, even the most severe cases, may be treated. The earlier that treatment can begin, the more effective it is.

 

As a result, however, there’s a need for robust biomarkers that will aid in improving diagnosis in order to accelerate the drug and/or medication discovery process for each patient with the disorder. These are objective, peripheral physiological indicators which presence can be used to predict the probability of onset or existence of depression, stratify according to severity or symptomatology, indicate predict and prognosis or monitor response to therapeutic interventions. The purpose of the following article is to demonstrate recent insights, current challenges and future prospects regarding the discovery of a variety of biomarkers for depression and how these can help improve diagnosis and treatment.

 

Biomarkers for Depression: Recent Insights, Current Challenges and Future Prospects

 

Abstract

 

A plethora of research has implicated hundreds of putative biomarkers for depression, but has not yet fully elucidated their roles in depressive illness or established what is abnormal in which patients and how biologic information can be used to enhance diagnosis, treatment and prognosis. This lack of progress is partially due to the nature and heterogeneity of depression, in conjunction with methodological heterogeneity within the research literature and the large array of biomarkers with potential, the expression of which often varies according to many factors. We review the available literature, which indicates that markers involved in inflammatory, neurotrophic and metabolic processes, as well as neurotransmitter and neuroendocrine system components, represent highly promising candidates. These may be measured through genetic and epigenetic, transcriptomic and proteomic, metabolomic and neuroimaging assessments. The use of novel approaches and systematic research programs is now required to determine whether, and which, biomarkers can be used to predict response to treatment, stratify patients to specific treatments and develop targets for new interventions. We conclude that there is much promise for reducing the burden of depression through further developing and expanding these research avenues.

 

Keywords: mood disorder, major depressive disorder, inflammation, treatment response, stratification, personalized medicine

 

Introduction

 

Challenges in Mental Health and Mood Disorders

 

Although psychiatry has a disease-related burden greater than any single other medical diagnostic category,1 a disparity of esteem is still apparent between physical and mental health across many domains including research funding2 and publication.3 Among the difficulties that mental health faces is a lack of consensus surrounding classification, diagnosis and treatment that stems from an incomplete understanding of the processes underlying these disorders. This is highly apparent in mood disorders, the category which comprises the single largest burden in mental health.3 The most prevalent mood disorder, major depressive disorder (MDD), is a complex, heterogeneous illness in which up to 60% of patients may experience some degree of treatment resistance that prolongs and worsens episodes.4 For mood disorders, and in the broader field of mental health, treatment outcomes would likely be improved by the discovery of robust, homogeneous subtypes within (and across) diagnostic categories, by which treatments could be stratified. In recognition of this, global initiatives to delineate functional subtypes are now in progress, such as the research domain criteria.5 It has been posited that biologic markers are priority candidates for subtyping mental disorders.6

 

Improving Response to Treatments for Depression

 

Despite an extensive range of treatment options for major depression, only approximately a third of patients with MDD achieve remission even when receiving optimal antidepressant treatment according to consensus guidelines and using measurement-based care, and rates of treatment response appear to fall with each new treatment.7 Furthermore, treatment-resistant depression (TRD) is associated with increased functional impairment, mortality, morbidity and recurrent or chronic episodes in the long term.8,9 Thus, obtaining improvements in treatment response at any clinical stage would afford wider benefits for overall outcomes in depression. Despite the substantial burden attributable to TRD, research in this area has been sparse. Definitions of TRD are not standardized, in spite of previous attempts:4 some criteria require only one treatment trial that fails to achieve a 50% symptom score reduction (from a validated measure of depression severity), while others require non-achievement of full remission or nonresponse to at least two adequately trialed antidepressants of different classes within an episode to be considered TRD.4,10 Furthermore, the staging and prediction of treatment resistance is improved by adding the key clinical features of severity and chronicity to the number of failed treatments.9,11 Nevertheless, this inconsistency in definition renders interpreting the research literature on TRD an even more complex task.

 

In order to improve response to treatments, it is clearly helpful to identify predictive risk factors of nonresponse. Some general predictors of TRD have been characterized, including a lack of full remission after previous episodes, comorbid anxiety, suicidality and early onset of depression, as well as personality (particularly low extraversion, low reward dependence and high neuroticism) and genetic factors.12 These findings are corroborated by reviews synthesizing the evidence separately for pharmacologic13 and psychological14 treatment for depression. Antidepressants and cognitive-behavioral therapies show approximately comparable efficacy,15 but due to their differing mechanisms of action might be expected to have different predictors of response. While early-life trauma has long been associated with poorer clinical outcomes and reduced responses to treatment,16 early indications suggest that people with a history of childhood trauma might respond better to psychological than pharmacologic therapies.17 Despite this, uncertainty prevails and little personalization or stratification of treatment has reached clinical practice.18

 

This review focuses on the evidence supporting the utility of biomarkers as potentially useful clinical tools to enhance treatment response for depression.

 

Biomarkers: Systems and Sources

 

Biomarkers provide a potential target for identifying predictors of response to various interventions.19 The evidence to date suggests that markers reflecting the activity of inflammatory, neurotransmitter, neurotrophic, neuroendocrine and metabolic systems may be able to predict mental and physical health outcomes in currently depressed individuals, but there is much inconsistency between findings.20 In this review, we focus on these five biologic systems.

 

To attain a full understanding of molecular pathways and their contribution in psychiatric disorders, it is now considered important to assess multiple biologic “levels”, in what is popularly referred to as an “omics” approach.21 Figure 1 provides a depiction of the different biologic levels at which each of the five systems can be assessed, and the potential sources of markers on which these assessments can be undertaken. However, note that while each system can be inspected at each omics level, the optimal sources of measurement clearly vary at each level. For example, neuroimaging provides a platform for indirect assessment of brain structure or function, while protein examinations in blood directly assess markers. Transcriptomics22 and metabolomics23 are increasingly popular, offering assessment of potentially huge numbers of markers, and the Human Microbiome Project is now attempting to identify all microorganisms and their genetic composition within humans.24 Novel technologies are enhancing our ability to measure these, including through additional sources; for example, hormones such as cortisol can now be assayed in hair or fingernails (providing a chronic indication) or sweat (providing a continuous measurement),25 as well as in blood, cerebrospinal fluid, urine and saliva.

 

Figure 1 Potential Biomarkers for Depression

 

Given the number of putative sources, levels and systems involved in depression, it is not surprising that the scale of biomarkers with translational potential is extensive. Particularly, when interactions between markers are considered, it is perhaps unlikely that examining single biomarkers in isolation will yield findings fruitful for improving clinical practice. Schmidt et al26 proposed the use of biomarker panels and, subsequently, Brand et al27 outlined a draft panel based on prior clinical and preclinical evidence for MDD, identifying 16 “strong” biomarker targets, each of which is rarely a single marker. They comprise reduced gray matter volume (in hippocampal, prefrontal cortex and basal ganglia regions), circadian cycle changes, hypercortisolism and other representations of hypothalamic–pituitary–adrenal (HPA) axis hyperactivation, thyroid dysfunction, reduced dopamine, noradrenaline or 5-hydroxyindoleacetic acid, increased glutamate, increased superoxide dismutase and lipid peroxidation, attenuated cyclic adenosine 3′,5′-monophosphate and mitogen-activated protein kinase pathway activity, increased proinflammatory cytokines, alterations to tryptophan, kynurenine, insulin and specific genetic polymorphisms. These markers have not been agreed by consensus and could be measured in various ways; it is clear that focused and systematic work must address this enormous task in order to prove their clinical benefits.

 

Aims of this Review

 

As a deliberately broad review, this article seeks to determine the overall needs for biomarker research in depression and the extent to which biomarkers hold real translational potential for enhancing response to treatments. We begin by discussing the most important and exciting findings in this field and direct the reader to more specific reviews pertaining to relevant markers and comparisons. We outline the current challenges faced in light of the evidence, in combination with needs for reducing the burden of depression. Finally, we look ahead to the important research pathways for meeting current challenges and their implications for clinical practice.

 

Recent Insights

 

The search for clinically useful biomarkers for people with depression has generated extensive investigation over the last half a century. The most commonly used treatments were conceived from the monoamine theory of depression; subsequently, neuroendocrine hypotheses gained much attention. In more recent years, the most prolific research has surrounded the inflammatory hypothesis of depression. However, a large number of relevant review articles have focused across all five systems; see Table 1 and below for a collection of recent insights across biomarker systems. While measured at many levels, blood-derived proteins have been examined most widely and provide a source of biomarker that is convenient, cost-effective and may be closer to translational potential than other sources; thus, more detail is given to biomarkers circulating in blood.

 

Table 1 Overview on Biomarkers for Depression

 

In a recent systematic review, Jani et al20 examined peripheral blood-based biomarkers for depression in association with treatment outcomes. Of only 14 studies included (searched up until early 2013), 36 biomarkers were studied of which 12 were significant predictors of mental or physical response indices in at least one investigation. Those identified as potentially representing risk factors for nonresponse included inflammatory proteins: low interleukin (IL)-12p70, ratio of lymphocyte to monocyte count; neuroendocrine markers (dexamethasone nonsuppression of cortisol, high circulating cortisol, reduced thyroid-stimulating hormone); neurotransmitter markers (low serotonin and noradrenaline); metabolic (low high-density lipoprotein cholesterol) and neurotrophic factors (reduced S100 calcium-binding protein B). Further to this, other reviews have reported on associations between additional biomarkers and treatment outcomes.19,28–30 A brief description of putative markers in each system is outlined in the subsequent sections and in Table 2.

 

Table 2 Biomarkers with Potential use for Depression

 

Inflammatory Findings in Depression

 

Since Smith’s seminal paper outlining the macrophage hypothesis,31 this established literature has found increased levels of various proinflammatory markers in depressed patients, which have been reviewed widely.32–37 Twelve inflammatory proteins have been evaluated in meta-analyses comparing depressed and healthy control populations.38–43

 

IL-6 (P<0.001 in all meta-analyses; 31 studies included) and CRP (P<0.001; 20 studies) appear frequently and reliably elevated in depression.40 Elevated tumor necrosis factor alpha (TNFα) was identified in early studies (P<0.001),38 but substantial heterogeneity rendered this inconclusive when accounting for more recent investigations (31 studies).40 IL-1β is even more inconclusively associated with depression, with meta-analyses suggesting higher levels in depression (P=0.03),41 high levels only in European studies42 or no differences from controls.40 Despite this, a recent article suggested particular translational implications for IL-1β,44 supported by an extremely significant effect of elevated IL-1β ribonucleic acid predicting a poor response to antidepressants;45 other findings above pertain to circulating blood-derived cytokines. The chemokine monocyte chemoattractant protein-1 has shown elevations in depressed participants in one meta-analysis.39 Interleukins IL-2, IL-4, IL-8, IL-10 and interferon gamma were not significantly different between depressed patients and controls at a meta-analytic level, but have nonetheless demonstrated potential in terms of altering with treatment: IL-8 has been reported as elevated in those with severe depression prospectively and cross-sectionally,46 different patterns of change in IL-10 and interferon gamma during treatment have occurred between early responders versus nonresponders,47 while IL-4 and IL-2 have decreased in line with symptom remission.48 In meta-analyses, small decreases alongside treatment have been demonstrated for IL-6, IL-1β, IL-10 and CRP.43,49,50 Additionally, TNFα may only reduce with treatment in responders, and a composite marker index may indicate increased inflammation in patients who subsequently do not respond to treatment.43 It is notable, however, that almost all of the research examining inflammatory proteins and treatment response utilize pharmacologic treatment trials. Thus, at least some inflammatory alterations during treatment are likely attributable to antidepressants. The precise inflammatory effects of different antidepressants have not yet been established, but evidence using CRP levels suggests individuals respond differently to specific treatments based on baseline inflammation: Harley et al51 reported elevated pretreatment CRP predicting a poor response to psychological therapy (cognitive–behavioral or interpersonal psychotherapy), but a good response to nortriptyline or fluoxetine; Uher et al52 replicated this finding for nortriptyline and identified the opposite effect for escitalopram. In contrast, Chang et al53 found higher CRP in early responders to fluoxetine or venlafaxine than nonresponders. Furthermore, patients with TRD and high CRP have responded better to the TNFα antagonist infliximab than those with levels in the normal range.54

 

Together, the evidence suggests that even when controlling for factors such as body mass index (BMI) and age, inflammatory responses appear aberrant in approximately one-third of patients with depression.55,56 The inflammatory system, however, is extremely complex, and there are numerous biomarkers representing different aspects of this system. Recently, additional novel cytokines and chemokines have yielded evidence of abnormalities in depression. These include: macrophage inhibitory protein 1a, IL-1a, IL-7, IL-12p70, IL-13, IL-15, eotaxin, granulocyte macrophage colony-stimulating factor,57 IL-5,58 IL-16,59 IL-17,60 monocyte chemoattractant protein-4,61 thymus and activation-regulated chemokine,62 eotaxin-3, TNFb,63 interferon gamma-induced protein 10,64 serum amyloid A,65 soluble intracellular adhesion molecule66 and soluble vascular cell adhesion molecule 1.67

 

Growth Factor Findings in Depression

 

In light of the potential importance of non-neurotrophic growth factors (such as those relating to angiogenesis), we refer to neurogenic biomarkers under the broader definition of growth factors.

 

Brain-derived neurotrophic factor (BDNF) is the most frequently studied of these. Multiple meta-analyses demonstrate attenuations of the BDNF protein in serum, which appear to increase alongside antidepressant treatment.68–71 The most recent of these analyses suggests that these BDNF aberrations are more pronounced in the most severely depressed patients, but that antidepressants appear to increase the levels of this protein even in the absence of clinical remission.70 proBDNF has been less widely studied than the mature form of BDNF, but the two appear to differ functionally (in terms of their effects on tyrosine receptor kinase B receptors) and recent evidence suggests that while mature BDNF may be reduced in depression, proBDNF may be overproduced.72 Nerve growth factor assessed peripherally has also been reported as lower in depression than in controls in a meta-analysis, but may not be altered by antidepressant treatment despite being most attenuated in patients with more severe depression.73 Similar findings have been reported in a meta-analysis for glial cell line-derived neurotrophic factor.74

 

Vascular endothelial growth factor (VEGF) has a role in promoting angiogenesis and neurogenesis along with other members of the VEGF family (eg, VEGF-C, VEGF-D) and has promise for depression.75 Despite inconsistent evidence, two meta-analyses have recently indicated elevations of VEGF in blood of depressed patients compared to controls (across 16 studies; P<0.001).76,77 However, low VEGF has been identified in TRD78 and higher levels have predicted nonresponse to antidepressant treatment.79 It is not understood why the levels of VEGF protein would be elevated, but it may partly be attributable to proinflammatory activity and/or increases in blood–brain barrier permeability in depressed states that causes reduced expression in cerebrospinal fluid.80 The relationship between VEGF and treatment response is unclear; a recent study found no relationship between either serum VEGF or BDNF with response or depression severity, despite decreases alongside antidepressant treatment.81 Insulin-like growth factor-1 is an additional factor with neurogenic functions that may be increased in depression, reflecting an imbalance in neurotrophic processes.82,83 Basic fibroblast growth factor (or FGF-2) is a member of the fibroblast growth factor family and appears higher in depressed than control groups.84 However, reports are not consistent; one found that this protein was lower in MDD than healthy controls, but reduced further alongside antidepressant treatment.85

 

Further growth factors that have not been sufficiently explored in depression include tyrosine kinase 2 and soluble fms-like tyrosine kinase-1 (also termed sVEGFR-1) which act in synergy with VEGF, and tyrosine kinase receptors (that bind BDNF) may be attenuated in depression.86 Placental growth factor is also part of the VEGF family, but has not been studied in systematically depressed samples to our knowledge.

 

Metabolic Biomarker Findings in Depression

 

The main biomarkers associated with metabolic illness include leptin, adiponectin, ghrelin, triglycerides, high-density lipoprotein (HDL), glucose, insulin and albumin.87 The associations between many of these and depression have been reviewed: leptin88 and ghrelin89 appear lower in depression than controls in the periphery and may increase alongside antidepressant treatment or remission. Insulin resistance may be increased in depression, albeit by small amounts.90 Lipid profiles, including HDL-cholesterol, appear altered in many patients with depression, including those without comorbid physical illness, though this relationship is complex and requires further elucidation.91 Additionally, hyperglycemia92 and hypoalbuminemia93 in depression have been reported in reviews.

 

Investigations of overall metabolic states are becoming more frequent using metabolomics panels of small molecules with the hope of finding a robust biochemical signature for psychiatric disorders. In a recent study using artificial intelligence modeling, a set of metabolites illustrating increased glucose–lipid signaling was highly predictive of an MDD diagnosis,94 supportive of previous studies.95

 

Neurotransmitter Findings in Depression

 

While the attention paid to monoamines in depression has yielded relatively successful treatments, no robust neurotransmitter markers have been identified to optimize treatment based on the selectivity of monoamine targets of antidepressants. Recent work points toward the serotonin (5-hydroxytryptamine) 1A receptor as potentially important for both diagnosis and prognosis of depression, pending new genetic and imaging techniques.96 There are new potential treatments targeting 5-hydroxytryptamine; for example, using a slow-release administration of 5-hydroxytryptophan.97 Increased transmission of dopamine interacts with other neurotransmitters to improve cognitive outcomes such as decision making and motivation.98 Similarly, the neurotransmitters glutamate, noradrenaline, histamine and serotonin may interact and activate as part of a depression-related stress response; this might decrease 5-hydroxytryptamine production through “flooding”. A recent review sets out this theory and suggests that in TRD, this could be reversed (and 5-HT restored) through multimodal treatment targeting multiple neurotransmitters.99 Interestingly, increases in serotonin do not always occur conjunctively with therapeutic antidepressant benefits.100 Despite this, neurotransmitter metabolites such as 3-methoxy-4-hydroxyphenylglycol, of noradrenaline, or homovanillic acid, of dopamine, have often been found to increase alongside reduction in depression with antidepressant treatment101,102 or that low levels of these metabolites predict a better response to SSRI treatment.102,103

 

Neuroendocrine Findings in Depression

 

Cortisol is the most common HPA axis biomarker to have been studied in depression. Numerous reviews have focused on the various assessments of HPA activity; overall, these suggest that depression is associated with hypercortisolemia and that the cortisol awakening response is often attenuated.104,105 This is supported by a recent review of chronic cortisol levels measured in hair, supporting the hypothesis of cortisol hyperactivity in depression but hypoactivity in other illnesses such as panic disorder.106 Furthermore, particularly, elevated cortisol levels may predict a poorer response to psychological107 and antidepressant108 treatment. Historically, the most promising neuroendocrine marker of prospective treatment response has been the dexamethasone suppression test, where cortisol nonsuppression following dexamethasone administration is associated with a lower likelihood of subsequent remission. However, this phenomenon has not been considered sufficiently robust for clinical application. Related markers corticotrophin-releasing hormone and adrenocorticotropin hormone as well as vasopressin are inconsistently found to be overproduced in depression and dehydroepiandrosterone is found to be attenuated; the ratio of cortisol to dehydroepiandrosterone may be elevated as a relatively stable marker in TRD, persisting after remission.109 Neuroendocrine hormone dysfunctions have long been associated with depression, and hypothyroidism may also play a causal role in depressed mood.110 Furthermore, thyroid responses can normalize with successful treatment for depression.111

 

Within the above, it is important also to consider signaling pathways across systems, such as glycogen synthase kinase-3, mitogen-activated protein kinase and cyclic adenosine 3′,5′-monophosphate, involved in synaptic plasticity112 and modified by antidepressants.113 Further potential biomarker candidates that span biologic systems particularly are measured using neuroimaging or genetics. In response to the lack of robust and meaningful genomic differences between depressed and nondepressed populations,114 novel genetic approaches such as polygenic scores115 or telomere length116,117 could prove more useful. Additional biomarkers gaining popularity are examining circadian cycles or chronobiologic biomarkers utilizing different sources. Actigraphy can provide an objective assessment of sleep and wake activity and rest through an accelerometer, and actigraphic devices can increasingly measure additional factors such as light exposure. This may be more useful for detection than commonly used subjective reports of patients and could provide novel predictors of treatment response.118 The question of which biomarkers are the most promising for translational use is a challenging one, which is expanded upon below.

 

Current Challenges

 

For each of these five neurobiological systems reviewed, the evidence follows a similar narrative: there are many biomarkers that exist that are associated in some respects with depression. These markers are frequently interrelated in a complex, difficult-to-model fashion. The evidence is inconsistent, and it is likely that some are epiphenomena of other factors and some are important in only a subset of patients. Biomarkers are likely to be useful through a variety of routes (eg, those that predict subsequent response to treatment, those indicating specific treatments as more likely to be effective or those that alter with interventions regardless of clinical improvements). Novel methods are required to maximize consistency and clinical applicability of biologic assessments in psychiatric populations.

 

Biomarker Variability

 

Variation of biomarkers over time and across situations pertains more to some types (eg, proteomics) than others (genomics). Standardized norms for many do not exist or have not been widely accepted. Indeed, the influence of environmental factors on markers frequently depends on genetic composition and other physiologic differences between people that cannot all be accounted for. This makes the assessment of biomarker activity, and identifying biologic abnormalities, difficult to interpret. Due to the number of potential biomarkers, many have not been measured widely or in a complete panel alongside other relevant markers.

 

Many factors have been reported to alter the protein levels across biologic systems in patients with affective disorders. Along with research-related factors such as duration and conditions of storage (which may cause degradation of some compounds), these include time of day measured, ethnicity, exercise,119 diet (eg, microbiome activity, especially provided that most blood biomarker studies do not require a fasting sample),120 smoking and substance use,121 as well as health factors (such as comorbid inflammatory, cardiovascular or other physical illnesses). For example, although heightened inflammation is observed in depressed but otherwise healthy individuals compared to nondepressed groups, depressed individuals who also have a comorbid immune-related condition frequently have even higher levels of cytokines than either those without depression or illness.122 Some prominent factors with probable involvement in the relationship between biomarkers, depression and treatment response are outlined below.

 

Stress. Both endocrine and immune responses have well-known roles in responding to stress (physiologic or psychological), and transient stress at the time of biologic specimen collection is rarely measured in research studies despite the variability of this factor between individuals that may be accentuated by current depressive symptoms. Both acute and chronic psychological stressors act as an immune challenge, accentuating inflammatory responses in the short and longer term.123,124 This finding extends to the experience of early-life stress, which has been associated with adult inflammatory elevations that are independent of stress experienced as an adult.125,126 During childhood traumatic experience, heightened inflammation has also been reported only in those children who were currently depressed.127 Conversely, people with depression and a history of childhood trauma may have blunted cortisol responses to stress, compared to those with depression and no early-life trauma.128 Stress-induced HPA axis alterations appear interrelated with cognitive function,129 as well as depression subtype or variation in HPA-related genes.130 Stress also has short- and long-term impairing effects on neurogenesis131 and other neural mechanisms.132 It is unclear precisely how childhood trauma affects biologic markers in depressed adults, but it is possible that early-life stress predisposes some individuals to enduring stress reactions in adulthood that are amplified psychologically and/or biologically.

 

Cognitive functioning. Neurocognitive dysfunctions occur frequently in people with affective disorders, even in unmedicated MDD.133 Cognitive deficits appear cumulative alongside treatment resistance.134 Neurobiologically, the HPA axis129 and neurotrophic systems135 are likely to play a key role in this relationship. Neurotransmitters noradrenaline and dopamine are likely important for cognitive processes such as learning and memory.136 Elevated inflammatory responses have been linked with cognitive decline, and likely affect cognitive functioning in depressive episodes,137 and in remission, through a variety of mechanisms.138 Indeed, Krogh et al139 proposed that CRP is more closely related to cognitive performance than to the core symptoms of depression.

 

Age, gender and BMI. The absence or presence, and direction of biologic differences between men and women has been particularly variable in the evidence to date. Neuroendocrine hormone variation between men and women interacts with depression susceptibility.140 A review of inflammation studies reported that controlling for age and gender did not affect patient-control differences in inflammatory cytokines (although the association between IL-6 and depression reduced as age increased, which is consistent with theories that inflammation generally heightens with age).41,141 VEGF differences between patients and controls are larger in studies assessing younger samples, while gender, BMI and clinical factors did not affect these comparisons at a meta-analytic level.77 However, the lack of adjustment for BMI in previous examinations of inflammation and depression appears to confound highly significant differences reported between these groups.41 Enlarged adipose tissue has been definitively demonstrated to stimulate cytokine production as well as being closely linked to metabolic markers.142 Because psychotropic medications may be associated with weight gain and a higher BMI, and these have been associated with treatment resistance in depression, this is an important area to examine.

 

Medication. Many biomarker studies in depression (both cross-sectional and longitudinal) have collected baseline specimens in unmedicated participants to reduce heterogeneity. However, many of these assessments are taken after a wash-out period from medication, which leaves the potentially significant confounding factor of residual changes in physiology, exacerbated by the extensive range of treatments available that may have had differing effects on inflammation. Some studies have excluded psychotropic, but not other medication use: in particular, the oral contraceptive pill is frequently permitted in research participants and not controlled for in analyses, which has recently been indicated to increase hormone and cytokine levels.143,144 Several studies indicate that antidepressant medications have effects on the inflammatory response,34,43,49,145–147 HPA-axis,108 neurotransmitter,148 and neurotrophic149 activity. However, the numerous potential treatments for depression have distinct and complex pharmacologic properties, suggesting there may be discrete biologic effects of different treatment options, supported by current data. It has been theorized that in addition to monoamine effects, specific serotonin-targeting medications (ie, SSRIs) are likely to target Th2 shifts in inflammation, and noradrenergic antidepressants (eg, SNRIs) effect a Th1 shift.150 It is not yet possible to determine the effects of individual or combination medications on biomarkers. These are likely mediated by other factors including the length of treatment (few trials assess long-term medication use), sample heterogeneity and not stratifying participants by response to treatment.

 

Heterogeneity

 

Methodological. As alluded to above, differences (between and within studies) in terms of which treatments (and combinations) the participants are taking and have taken previously are bound to introduce heterogeneity into research findings, particularly in biomarker research. In addition to this, many other design and sample characteristics vary across studies, thus augmenting the difficulty with interpreting and attributing findings. These include biomarker measurement parameters (eg, assay kits) and methods of collecting, storing, processing and analyzing markers in depression. Hiles et al141 examined some sources of inconsistency in the literature on inflammation and found that accuracy of depression diagnosis, BMI and comorbid illnesses were most important to account for in assessing peripheral inflammation between depressed and nondepressed groups.

 

Clinical. The extensive heterogeneity of depressed populations is well documented151 and is a critical contributor to contrasting findings within the research literature. It is probable that even within diagnoses, abnormal biologic profiles are confined to subsets of individuals that may not be stable over time. Cohesive subgroups of people suffering with depression may be identifiable through a combination of psychological and biologic factors. Below, we outline the potential for exploring subgroups in meeting the challenges that biomarker variability and heterogeneity pose.

 

Subtypes within Depression

 

Thus far, no homogenous subgroups within depression episodes or disorders have been reliably able to distinguish between patients based on symptom presentations or treatment responsiveness.152 The existence of a subgroup in whom biologic aberrations are more pronounced would help to explain the heterogeneity between previous studies and could catalyze the path toward stratified treatment. Kunugi et al153 have proposed a set of four potential subtypes based on the role of different neurobiological systems displaying clinically relevant subtypes in depression: those with hypercortisolism presenting with melancholic depression, or hypocortisolism reflecting an atypical subtype, a dopamine-related subset of patients who may present prominently with anhedonia (and could respond well to, eg, aripiprazole) and an inflammatory subtype characterized by elevated inflammation. Many articles focusing on inflammation have specified the case for the existence of an “inflammatory subtype” within depression.55,56,154,155 Clinical correlates of elevated inflammation are as yet undetermined and few direct attempts have been made to discover which participants may comprise this cohort. It has been proposed that people with atypical depression could have higher levels of inflammation than the melancholic subtype,156 which is perhaps not in line with findings regarding the HPA axis in melancholic and atypical subtypes of depression. TRD37 or depression with prominent somatic symptoms157 has also been posited as a potential inflammatory subtype, but neurovegetative (sleep, appetite, libido loss), mood (including low mood, suicidality and irritability) and cognitive symptoms (including affective bias and guilt)158 all appear related to biologic profiles. Further potential candidates for an inflammatory subtype involve the experience of sickness behavior-like symptoms159,160 or a metabolic syndrome.158

 

The propensity toward (hypo) mania may distinguish biologically between patients suffering from depression. Evidence now suggests that bipolar illnesses are a multifaceted group of mood disorders, with bipolar subsyndromal disorder found more prevalently than was previously recognized.161 Inaccurate and/or delayed detection of bipolar disorder has recently been highlighted as a major problem in clinical psychiatry, with the average time to correct diagnosis frequently exceeding a decade162 and this delay causing greater severity and cost of overall illness.163 With the majority of patients with bipolar disorder presenting initially with one or more depressive episodes and unipolar depression being the most frequent misdiagnosis, the identification of factors that might differentiate between unipolar and bipolar depression has substantial implications.164 Bipolar spectrum disorders likely have been undetected in some previous MDD biomarker investigations, and smatterings of evidence have indicated differentiation of HPA axis activity109 or inflammation165,166 between bipolar and unipolar depression. However, these comparisons are scarce, possess small sample sizes, identified nonsignificant trend effects or recruited populations that were not well characterized by diagnosis. These investigations also do not examine the role of treatment responsiveness in these relationships.

 

Both bipolar disorders167 and treatment resistance168 are not dichotomous constructs and lie on continua, which increases the challenge of subtype identification. Apart from subtyping, it is worth noting that many biologic abnormalities observed in depression are similarly found in patients with other diagnoses. Thus, transdiagnostic examinations are also potentially important.

 

Biomarker Measurement Challenges

 

Biomarker selection. The large number of potentially useful biomarkers presents a challenge for psychobiology in determining which markers are implicated in which way and for whom. To increase the challenge, relatively few of these biomarkers have been subject to sufficient investigation in depression, and for most, their precise roles in healthy and clinical populations are not well understood. Despite this, a number of attempts have been made to propose promising biomarker panels. In addition to Brand et al’s 16 sets of markers with strong potential,27 Lopresti et al outline an additional extensive set of oxidative stress markers with potential for improving treatment response.28 Papakostas et al defined a priori a set of nine serum markers spanning biologic systems (BDNF, cortisol, soluble TNFα receptor type II, alpha1 antitrypsin, apolipoprotein CIII, epidermal growth factor, myeloperoxidase, prolactin and resistin) in validation and replication samples with MDD. Once combined, a composite measure of these levels was able to distinguish between MDD and control groups with 80%–90% accuracy.169 We propose that even these do not cover all potential candidates in this field; see Table 2 for a nonexhaustive delineation of biomarkers with potential for depression, containing both those with an evidence base and promising novel markers.

 

Technology. Due to technologic advances, it is now possible (indeed, convenient) to measure a large array of biomarkers simultaneously at a lower cost and with higher sensitivity than has been the case previously. At present, this capability to measure numerous compounds is ahead of our ability to effectively analyze and interpret the data,170 something that will continue with the rise in biomarker arrays and new markers such as with metabolomics. This is largely due to a lack of understanding about the precise roles of and the interrelationships between markers, and an insufficient grasp of how related markers associate across different biologic levels (eg, genetic, transcription, protein) within and between individuals. Big data using new analytical approaches and standards will assist with addressing this, and new methodologies are being proposed; one example is the development of a statistical approach grounded in flux-based analysis to discover new potential metabolic markers based on their reactions between networks and integrate gene expression with metabolite data.171 Machine learning techniques are already being applied and will assist with models using biomarker data to predict treatment outcomes in studies with big data.172

 

Aggregating biomarkers. Examining an array of biomarkers simultaneously is an alternative to inspecting isolated markers that could provide a more accurate viewpoint into the complex web of biologic systems or networks.26 Also, to assist with disentangling contrasting evidence in this literature to date (particularly, where biomarker networks and interactions are well understood), biomarker data can then be aggregated or indexed. One challenge is in identifying the optimum method of conducting this, and it may require enhancements in technology and/or novel analytical techniques (see the “Big data” section). Historically, ratios between two distinct biomarkers have yielded interesting findings.109,173 Few attempts have been made to aggregate biomarker data on a larger scale, such as those using principal component analysis of proinflammatory cytokine networks.174 In a meta-analysis, proinflammatory cytokines have been converted into a single-effect size score for each study, and overall showed significantly higher inflammation before antidepressant treatment, predicting subsequent nonresponse in outpatient studies. Composite biomarker panels are both a challenge and opportunity for future research to identify meaningful and reliable findings that can be applied to improve treatment outcomes.43 A study by Papakostas et al took an alternative approach, selecting a panel of heterogeneous serum biomarkers (of inflammatory, HPA axis and metabolic systems) that had been indicated to differ between depressed and control individuals in a previous study and composited these into a risk score which differed in two independent samples and a control group with >80% sensitivity and specificity.169

 

Big data. The use of big data is probably necessary for addressing the current challenges outlined surrounding heterogeneity, biomarker variability, identifying the optimal markers and bringing the field toward translational, applied research in depression. However, as outlined above, this brings technological and scientific challenges.175 The health sciences have only recently begun using big data analytics, a decade or so later than in the business sector. However, studies such as iSPOT-D152 and consortia such as the Psychiatric Genetics Consortium176 are progressing with our understanding of biologic mechanisms in psychiatry. Machine-learning algorithms have, in very few studies, started to be applied to biomarkers for depression: a recent investigation pooled data from >5,000 participants of 250 biomarkers; after multiple imputation of data, a machine-learning boosted regression was conducted, indicating 21 potential biomarkers. Following further regression analyses, three biomarkers were selected as associating most strongly with depressive symptoms (highly variable red blood cell size, serum glucose and bilirubin levels). The authors conclude that big data can be used effectively for generating hypotheses.177 Larger biomarker phenotyping projects are now underway and will help to advance our journey into the future of the neurobiology of depression.

 

Future Prospects

 

Biomarker Panel Identification

 

The findings in the literature to date require replication in large-scale studies. This is particularly true for novel biomarkers, such as the chemokine thymus and activation-regulated chemokine and the growth factor tyrosine kinase 2 which, to our knowledge, have not been investigated in clinically depressed and healthy control samples. Big data studies must assay comprehensive biomarker panels and use sophisticated analysis techniques to fully ascertain the relationships between markers and those factors which modify them in clinical and nonclinical populations. Additionally, large-scale replications of principal component analysis might establish highly correlated groups of biomarkers and could also inform the use of “composites” in biologic psychiatry, which may enhance the homogeneity of future findings.

 

Discovery of Homogenous Subtypes

 

Regarding biomarker selection, multiple panels may be required for different potential pathways that research could implicate. Taken together, the current evidence indicates that biomarker profiles are assuredly, but abstrusely altered in a subpopulation of individuals currently suffering from depression. This may be established within or across diagnostic categories, which would account for some inconsistency of findings that can be observed in this literature. Quantifying a biologic subgroup (or subgroups) may most effectively be facilitated by a large cluster analysis of biomarker network panels in depression. This would illustrate within-population variability; latent class analyses could exhibit distinct clinical characteristics based on, for example, inflammation.

 

Specific Treatment Effects on Inflammation and Response

 

All commonly prescribed treatments for depression should be comprehensively assessed for their specific biologic effects, also accounting for the effectiveness of treatment trials. This may enable constructs relating to biomarkers and symptom presentations to predict outcomes to a variety of antidepressant treatments in a more personalized fashion, and may be possible in the context of both unipolar and bipolar depression. This is likely to be useful for new potential treatments as well as currently indicated treatments.

 

Prospective Determination of Treatment Response

 

Use of the above techniques is likely to result in an improved ability to forecast treatment resistance prospectively. More authentic and persistent (eg, long-term) measures of treatment response may contribute to this. Assessment of other valid measures of patient well-being (such as quality of life and everyday functioning) could provide a more holistic assessment of treatment outcome that may associate more closely with biomarkers. While biologic activity alone might not be able to distinguish treatment responders from nonresponders, concurrent measurement of biomarkers with psychosocial or demographic variables could be integrated with biomarker information in developing a predictive model of insufficient treatment response. If a reliable model is developed to predict response (either for the depressed population or a subpopulation) and is validated retrospectively, a translational design can establish its applicability in a large controlled trial.

 

Toward Stratified Treatments

 

At present, patients with depression are not systematically directed to receive an optimized intervention program. If validated, a stratified trial design could be employed to test a model to predict nonresponse and/or to determine where a patient needs to be triaged in a stepped care model. This could be useful in both standardized and naturalistic treatment settings, across different types of intervention. Ultimately, a clinically viable model could be developed to provide individuals with the most appropriate treatment, to recognize those who are likely to develop refractory depression and supply enhanced care and monitoring to these patients. Patients identified as being at risk for treatment resistance may be prescribed a concomitant psychological and pharmacologic therapy or combination pharmacotherapy. As a speculative example, participants with no proinflammatory cytokine elevations might be indicated to receive psychological rather than pharmacologic therapy, while a subset of patients with particularly high inflammation could receive an anti-inflammatory agent in augmentation to standard treatment. Similar to stratification, personalized treatment-selection strategies may be possible in the future. For example, a particular depressed individual might have markedly high TNFα levels, but no other biologic abnormalities, and could benefit from short-term treatment with a TNFα antagonist.54 Personalized treatment may also entail monitoring biomarker expression during treatment to inform possible intervention changes, the length of continuation therapy required or to detect early markers of relapse.

 

Novel Treatment Targets

 

There are a huge number of potential treatments that could be effective for depression, which have not been adequately examined, including novel or repurposed interventions from other medical disciplines. Some of the most popular targets have been in anti-inflammatory medications such as celecoxib (and other cyclooxygenase-2 inhibitors), TNFα antagonists etanercept and infliximab, minocycline or aspirin. These appear promising.178 Antiglucocorticoid compounds, including ketoconazole179 and metyrapone,180 have been investigated for depression, but both have drawbacks with their side effect profile and the clinical potential of metyrapone is uncertain. Mifepristone181 and the corticosteroids fludrocortisone and spironolactone,182 and dexamethasone and hydrocortisone183 may also be effective in treating depression in the short term. Targeting glutamate N-methyl-d-aspartate receptor antagonists, including ketamine, might represent efficacious treatments in depression.184 Omega-3 polyunsaturated fatty acids influence inflammatory and metabolic activity and appear to demonstrate some effectiveness for depression.185 It is possible that statins may have antidepressant effects186 through relevant neurobiological pathways.187

 

In this way, the biochemical effects of antidepressants (see the “Medication” section) have been utilized for clinical benefits in other disciplines: particularly gastroenterological, neurologic and nonspecific symptom illnesses.188 Anti-inflammatory effects of antidepressants may represent part of the mechanism for these benefits. Lithium has also been suggested to reduce inflammation, critically through glycogen synthase kinase-3 pathways.189 A focus on these effects could prove informative for a depression biomarker signature and, in turn, biomarkers could represent surrogate markers for novel drug development.

 

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Dr. Alex Jimenez’s Insight

Depression is a mental health disorder characterized by severe symptoms which affect mood, including loss of interest in activities. Recent research studies, however, have found that it may be possible to diagnose depression using more than just a patient’s behavioral symptoms. According to the researchers, identifying easily obtainable biomarkers which could more accurately diagnose depression is fundamental towards improving a patient’s overall health and wellness. By way of instance, clinical findings suggest that individuals with major depressive disorder, or MDD, have lower levels of the molecule acetyl-L-carnitine, or LAC, in their blood than healthy controls. Ultimately, establishing biomarkers for depression could potentially help better determine who is at risk of developing the disorder as well as help healthcare professionals determine the best treatment option for a patient with depression.

 

Conclusion

 

The literature indicates that approximately two-thirds of patients with depression do not achieve remission to an initial treatment and that the likelihood of nonresponse increases with the number of treatments trialed. Providing ineffective therapies has substantial consequences for individual and societal cost, including persistent distress and poor well-being, risk of suicide, loss of productivity and wasted health care resources. The vast literature in depression indicates a huge number of biomarkers with the potential to improve treatment for people with depression. In addition to neurotransmitter and neuroendocrine markers which have been subject to widespread study for many decades, recent insights highlight the inflammatory response (and the immune system more generally), metabolic and growth factors as importantly involved in depression. However, excessive contrasting evidence illustrates that there are a number of challenges needing to be tackled before biomarker research can be applied in order to improve the management and care of people with depression. Due to the sheer complexity of biologic systems, simultaneous examinations of a comprehensive range of markers in large samples are of considerable benefit in discovering interactions between biologic and psychological states across individuals. Optimizing the measurement of both neurobiological parameters and clinical measures of depression is likely to facilitate greater understanding. This review also highlights the importance of examining potentially modifying factors (such as illness, age, cognition and medication) in gleaning a coherent understanding of the biology of depression and mechanisms of treatment resistance. It is likely that some markers will show most promise for predicting treatment response or resistance to specific treatments in a subgroup of patients, and the concurrent measurement of biologic and psychological data may enhance the ability to prospectively identify those at risk for poor treatment outcomes. Establishing a biomarker panel has implications for boosting diagnostic accuracy and prognosis, as well as for individualizing treatments at the earliest practicable stage of depressive illness and developing effective novel treatment targets. These implications may be confined to subgroups of depressed patients. The pathways toward these possibilities complement recent research strategies to link clinical syndromes more closely to underlying neurobiological substrates.6 Apart from reducing heterogeneity, this may facilitate a shift toward parity of esteem between physical and mental health. It is clear that although much work is needed, establishment of the relationship between relevant biomarkers and depressive disorders has substantial implications for reducing the burden of depression at an individual and societal level.

 

Acknowledgments

 

This report represents independent research funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.

 

Footnotes

 

Disclosure. AHY has in the last 3 years received honoraria for speaking from Astra Zeneca (AZ), Lundbeck, Eli Lilly, Sunovion; honoraria for consulting from Allergan, Livanova and Lundbeck, Sunovion, Janssen; and research grant support from Janssen and UK funding agencies (NIHR, MRC, Wellcome Trust). AJC has in the last 3 years received honoraria for speaking from Astra Zeneca (AZ), honoraria for consulting from Allergan, Livanova and Lundbeck, and research grant support from Lundbeck and UK funding agencies (NIHR, MRC, Wellcome Trust).

 

The authors report no other conflicts of interest in this work.

 

In conclusion, while numerous research studies have found hundreds of biomarkers for depression, not many have established their role in depressive illness or how exactly biologic information could be utilized to enhance diagnosis, treatment and prognosis. However, the article above reviews the available literature on the biomarkers involved during other processes and compares the clinical findings to that of depression. Furthermore, new findings on biomarkers for depression may help better diagnose depression in order to follow up with better treatment. Information referenced from the National Center for Biotechnology Information (NCBI). The scope of our information is limited to chiropractic as well as to spinal injuries and conditions. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at 915-850-0900 .

 

Curated by Dr. Alex Jimenez

 

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Additional Topics: Back Pain

Back pain is one of the most prevalent causes for disability and missed days at work worldwide. As a matter of fact, back pain has been attributed as the second most common reason for doctor office visits, outnumbered only by upper-respiratory infections. Approximately 80 percent of the population will experience some type of back pain at least once throughout their life. The spine is a complex structure made up of bones, joints, ligaments and muscles, among other soft tissues. Because of this, injuries and/or aggravated conditions, such as herniated discs, can eventually lead to symptoms of back pain. Sports injuries or automobile accident injuries are often the most frequent cause of back pain, however, sometimes the simplest of movements can have painful results. Fortunately, alternative treatment options, such as chiropractic care, can help ease back pain through the use of spinal adjustments and manual manipulations, ultimately improving pain relief.

 

 

 

blog picture of cartoon paperboy big news

 

 

EXTRA IMPORTANT TOPIC: Low Back Pain Management

 

MORE TOPICS: EXTRA EXTRA: Chronic Pain & Treatments

 

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160. Maes M, Berk M, Goehler L, et al. Depression and sickness behavior are Janus-faced responses to shared inflammatory pathways. BMC Med. 2012;10:66. [PMC free article] [PubMed]
161. Merikangas KR, Jin R, He J-P, et al. Prevalence and correlates of bipolar spectrum disorder in the world mental health survey initiative. Arch Gen Psychiatry. 2011;68(3):241–251. [PMC free article][PubMed]
162. Hirschfeld RM, Lewis L, Vornik LA. Perceptions and impact of bipolar disorder: how far have we really come? Results of the national depressive and manic-depressive association 2000 survey of individuals with bipolar disorder. J Clin Psychiatry. 2003;64(2):161–174. [PubMed]
163. Young AH, MacPherson H. Detection of bipolar disorder. Br J Psychiatry. 2011;199(1):3–4.[PubMed]
164. Vöhringer PA, Perlis RH. Discriminating between bipolar disorder and major depressive disorder. Psychiatr Clin North Am. 2016;39(1):1–10. [PubMed]
165. Becking K, Spijker AT, Hoencamp E, Penninx BW, Schoevers RA, Boschloo L. Disturbances in hypothalamic-pituitary-adrenal axis and immunological activity differentiating between unipolar and bipolar depressive episodes. PLoS One. 2015;10(7):e0133898. [PMC free article] [PubMed]
166. Huang TL, Lin FC. High-sensitivity C-reactive protein levels in patients with major depressive disorder and bipolar mania. Prog NeuroPsychopharmacol Biol Psychiatry. 2007;31(2):370–372. [PubMed]
167. Angst J, Gamma A, Endrass J. Risk factors for the bipolar and depression spectra. Acta Psychiatr Scand. 2003;418:15–19. [PubMed]
168. Fekadu A, Wooderson S, Donaldson C, et al. A multidimensional tool to quantify treatment resistance in depression: the Maudsley staging method. J Clin Psychiatry. 2009;70(2):177. [PubMed]
169. Papakostas G, Shelton R, Kinrys G, et al. Assessment of a multi-assay, serum-based biological diagnostic test for major depressive disorder: a pilot and replication study. Mol Psychiatry. 2013;18(3):332–339. [PubMed]
170. Fan J, Han F, Liu H. Challenges of big data analysis. Natl Sci Rev. 2014;1(2):293–314.[PMC free article] [PubMed]
171. Li L, Jiang H, Qiu Y, Ching WK, Vassiliadis VS. Discovery of metabolite biomarkers: flux analysis and reaction-reaction network approach. BMC Syst Biol. 2013;7(Suppl 2):S13. [PMC free article][PubMed]
172. Patel MJ, Khalaf A, Aizenstein HJ. Studying depression using imaging and machine learning methods. NeuroImage Clin. 2016;10:115–123. [PMC free article] [PubMed]
173. Lanquillon S, Krieg JC, Bening-Abu-Shach U, Vedder H. Cytokine production and treatment response in major depressive disorder. Neuropsychopharmacol. 2000;22(4):370–379. [PubMed]
174. Lindqvist D, Janelidze S, Erhardt S, Träskman-Bendz L, Engström G, Brundin L. CSF biomarkers in suicide attempters–a principal component analysis. Acta Psychiatr Scand. 2011;124(1):52–61. [PubMed]
175. Hidalgo-Mazzei D, Murru A, Reinares M, Vieta E, Colom F. Big data in mental health: a challenging fragmented future. World Psychiatry. 2016;15(2):186–187. [PMC free article] [PubMed]
176. Consortium C-DGotPG Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet. 2013;381(9875):1371–1379. [PMC free article] [PubMed]
177. Dipnall JF, Pasco JA, Berk M, et al. Fusing data mining, machine learning and traditional statistics to detect biomarkers associated with depression. PLoS One. 2016;11(2):e0148195. [PMC free article][PubMed]
178. Köhler O, Benros ME, Nordentoft M, et al. Effect of anti-inflammatory treatment on depression, depressive symptoms, and adverse effects: a systematic review and meta-analysis of randomized clinical trials. JAMA Psychiatry. 2014;71(12):1381–1391. [PubMed]
179. Wolkowitz OM, Reus VI, Chan T, et al. Antiglucocorticoid treatment of depression: double-blind ketoconazole. Biol Psychiatry. 1999;45(8):1070–1074. [PubMed]
180. McAllister-Williams RH, Anderson IM, Finkelmeyer A, et al. Antidepressant augmentation with metyrapone for treatment-resistant depression (the ADD study): a double-blind, randomised, placebo-controlled trial. Lancet Psychiatry. 2016;3(2):117–127. [PubMed]
181. Gallagher P, Young AH. Mifepristone (RU-486) treatment for depression and psychosis: A review of the therapeutic implications. Neuropsychiatr Dis Treat. 2006;2(1):33–42. [PMC free article] [PubMed]
182. Otte C, Hinkelmann K, Moritz S, et al. Modulation of the mineralocorticoid receptor as add-on treatment in depression: a randomized, double-blind, placebo-controlled proof-of-concept study. J Psychiatr Res. 2010;44(6):339–346. [PubMed]
183. Ozbolt LB, Nemeroff CB. HPA axis modulation in the treatment of mood disorders. Psychiatr Disord. 2013;51:1147–1154.
184. Walker AK, Budac DP, Bisulco S, et al. NMDA receptor blockade by ketamine abrogates lipopolysaccharide-induced depressive-like behavior in C57BL/6J mice. Neuropsychopharmacol. 2013;38(9):1609–1616. [PMC free article] [PubMed]
185. Lespérance F, Frasure-Smith N, St-André E, Turecki G, Lespérance P, Wisniewski SR. The efficacy of omega-3 supplementation for major depression: a randomized controlled trial. J Clin Psychiatry. 2010;72(8):1054–1062. [PubMed]
186. Kim S, Bae K, Kim J, et al. The use of statins for the treatment of depression in patients with acute coronary syndrome. Transl Psychiatry. 2015;5(8):e620. [PMC free article] [PubMed]
187. Shishehbor MH, Brennan M-L, Aviles RJ, et al. Statins promote potent systemic antioxidant effects through specific inflammatory pathways. Circulation. 2003;108(4):426–431. [PubMed]
188. Mercier A, Auger-Aubin I, Lebeau J-P, et al. Evidence of prescription of antidepressants for non-psychiatric conditions in primary care: an analysis of guidelines and systematic reviews. BMC Family Practice. 2013;14(1):55. [PMC free article] [PubMed]
189. Freland L, Beaulieu J-M. Inhibition of GSK3 by lithium, from single molecules to signaling networks. Front Mol Neurosci. 2012;5:14. [PMC free article] [PubMed]
190. Horowitz MA, Zunszain PA. Neuroimmune and neuroendocrine abnormalities in depression: two sides of the same coin. Ann N Y Acad Sci. 2015;1351(1):68–79. [PubMed]
191. Juruena MF, Cleare AJ. Overlap between atypical depression, seasonal affective disorder and chronic fatigue syndrome. Rev Bras Psiquiatr. 2007;29:S19–S26. [PubMed]
192. Castrén E, Kojima M. Brain-derived neurotrophic factor in mood disorders and antidepressant treatments. Neurobiol Dis. 2017;97(Pt B):119–126. [PubMed]
193. Pan A, Keum N, Okereke OI, et al. Bidirectional association between depression and metabolic syndrome a systematic review and meta-analysis of epidemiological studies. Diabetes Care. 2012;35(5):1171–1180. [PMC free article] [PubMed]
194. Carvalho AF, Rocha DQ, McIntyre RS, et al. Adipokines as emerging depression biomarkers: a systematic review and meta-analysis. J Psychiatric Res. 2014;59:28–37. [PubMed]
195. Wise T, Cleare AJ, Herane A, Young AH, Arnone D. Diagnostic and therapeutic utility of neuroimaging in depression: an overview. Neuropsychiatr Dis Treat. 2014;10:1509–1522.[PMC free article] [PubMed]
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198. Pierscionek T, Adekunte O, Watson S, Ferrier N, Alabi A. Role of corticosteroids in the antidepressant response. ChronoPhys Ther. 2014;4:87–98.
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Facetogenic Pain, Headaches, Neuropathic Pain And Osteoarthritis

Facetogenic Pain, Headaches, Neuropathic Pain And Osteoarthritis

El Paso, TX. Chiropractor Dr. Alexander Jimenez takes a look at various conditions that can cause chronic pain. These include:

facetogenic neuropathic, osteoarthritis and headaches pain el paso tx.
facetogenic neuropathic, osteoarthritis and headaches pain el paso tx.
facetogenic neuropathic, osteoarthritis and headaches pain el paso tx.
facetogenic neuropathic, osteoarthritis and headaches pain el paso tx.
facetogenic neuropathic, osteoarthritis and headaches pain el paso tx.Abstract

Arthritis pain is a complex phenomenon involving intricate neurophysiological processing at all levels of the pain pathway. The treatment options available to alleviate joint pain are fairly limited and most arthritis patients report only modest pain relief with current treatments. A better understanding of the neural mechanisms responsible for musculoskeletal pain and the identification of new targets will help in the development of future pharmacological therapies. This article reviews some of the latest research into factors which contribute to joint pain and covers areas such as cannabinoids, proteinase activated receptors, sodium channels, cytokines and transient receptor potential channels. The emerging hypothesis that osteoarthritis may have a neuropathic component is also discussed.

Introduction

The world health organization ranks musculoskeletal disorders as the most frequent cause of disability in the modern world, affecting one in three adults [1]. Even more alarming is that the prevalence of these diseases is rising while our knowledge of their underlying causes is fairly rudimentary.

facetogenic neuropathic, osteoarthritis and headaches pain el paso tx.

Fig. 1 A schematic illustrating some of the targets known to modulate joint pain. Neuromodulators can be released from nerve terminals as well as mast cells and macrophages to alter afferent mechanosensitivity. Endovanilloids, acid and noxious heat can activate transient receptor potential vanilloid type 1 (TRPV1) ion channels leading to the release of algogenic substance P (SP) which subsequently binds toneurokinin-1 (NK1) receptors. Proteases can cleave and stimulate pro-tease activated receptors (PARs). Thus far, PAR2and PAR4have been shown to sensitize joint primary afferents. The endocannabinoid anandamide (AE) is produced on demand and synthesized from N-arachidonylphosphatidylethanolamine (NAPE) under the enzymaticaction of phospholipases. A portion of AE then binds to cannabinoid-1 (CB1) receptors leading to neuronal desensitization. Unbound AE is rapidly taken up by an anandamide membrane transporter (AMT)before being broken down by a fatty acid amide hydrolase (FAAH)into ethanolamine (Et) and arachidonic acid (AA). The cytokines tumour necrosis factor-α(TNF-α), interleukin-6 (IL-6) and interleukin1-beta (IL-1β) can bind to their respective receptors to enhance pain transmission. Finally, there are tetrodotoxin (TTX)-resistant sodium channels (Nav1.8) involved in neuronal sensitization.

Patients yearn for their chronic pain to disappear; however, currently-prescribed analgesics are largely ineffective and are accompanied by a wide range of unwanted side effects.As such, millions of people worldwide are suffering from the debilitating effects of joint pain, for which there is no satisfactory treatment [2].

There are more than 100 different forms of arthritis with osteoarthritis (OA) being the most common. OA is a progressively degenerative joint disease that causes chronic pain and loss of function. Commonly, OA is the inability of the joint to repair damage effectively in response to excessive forces being placed on it. The biological and psychosocial factors that comprise chronic OA pain are not well understood, al-though ongoing research continues to unravel the complex nature of disease symptoms [2]. Current therapeutics, such as non-steroidal anti-inflammatory drugs (NSAIDs), provide some symptomatic relief, reducing the pain for short periods of time, but do not alleviate pain across the lifespan of the patient. Furthermore, high-dose NSAIDs cannot be taken repeatedly over many years, as this can lead to renal toxicity and gastrointestinal bleeding.

Traditionally, arthritis research has focused largely on the articular cartilage as a primary target for therapeutic development of novel OA drugs for disease modification. This“chondrocentric” focus has shed new light on the intricate biochemical and biomechanical factors that influence chondrocyte behavior in diseased joints. However, as articular cartilage is aneural and avascular, this tissue is unlikely to be the source of OA pain. This fact, coupled with the findings that there is no correlation between the damage of articular cartilage and pain in OA patients [3,4], or in preclinical models of OA [5••], has caused a shift in focus to develop drugs for effective pain control. This article will review the latest findings in joint pain research and highlight some of the emerging targets that may be the future of arthritis pain management (summarized in Fig. 1)

Cytokines

The actions of various cytokines in joint neurophysiology studies have featured quite prominently recently. Interleukin-6 (IL-6), for example, is a cytokine that typically binds to the membrane-bound IL-6 receptor (IL-6R). IL-6 can also signal by binding with a soluble IL-6R (sIL-6R) to produce an IL-6/sIL-6R complex. This IL-6/sIL-6R complex subsequent lybinds to a transmembrane glycoprotein subunit 130(gp130) thereby allowing IL-6 to signal in cells that do not constitutively express membrane-bound IL-6R [25,26]. IL-6 and sIL-6R are known to be key players in systemic inflammation and arthritis, as up regulation of both has been found in the serum and synovial fluid of RA patients [27–29]. Recently, Vazquez et al.observed that co-administration of IL-6/sIL-6R into rat knees caused inflammation-evoked pain, as revealed by an increase in the response of spinal dorsal horn neurons to mechanical stimulation of the knee and other parts of the hindlimb [30].Spinal neurone hyperexcitability was also seen when IL-6/sIL-6R was applied locally to the spinal cord. Spinal application of soluble gp130 (which would “mop up”IL-6/sIL-6R complexes thereby reducing trans signaling) inhibited IL-6/sIL-6R-induced central sensitization. Acute application of soluble gp130 alone, however, did not reduce the neuronal responses to already established joint inflammation.

The transient receptor potential (TRP) channels are a group of non-selective cation channels that act as integrators of various physiological and pathophysiological processes. In addition to thermosensation, chemosensation and mechanosensation, TRP channels are involved in the modulation of pain and inflammation. TRP vanilloid-1 (TRPV1) ion channels have been shown to contribute to joint inflammatory pain as thermal hyperalgesia was not evocable in TRPV1−/−monoarthritic mice [31]. Similarly, TRP ankyrin-1 (TRPA1)ion channels are involved in arthritic mechanohypersensitivity as blockade of the receptor with selective antagonistsattenuated mechanical pain in the Freund’s complete adjuvant model of inflammation [32,33]. Further evidence thatTRPV1 may be involved in the neurotransmission of OA pain comes from studies in which neuronal TRPV1 expression is elevated in the sodium monoiodoacetate model of OA [34]. Inaddition, systemic administration of the TRPV1 antagonist A-889425 reduced the evoked and spontaneous activity ofspinal-wide dynamic range and nociception-specific neuronesin the monoiodoacetate model [35]. These data suggest that endovanilloids could be involved in central sensitization processes associated with OA pain.

There are currently known to be at least four polymorphisms in the gene that encodes TRPV1, which can lead toan alteration in the structure of the ion channel and impaired function. One particular polymorphism (rs8065080) alters the sensitivity of TRPV1 to capsaicin and individuals carrying this polymorphism are less sensitive to thermal hyperalgesia [36]. Based on this genetic anomaly, a recent study examined whether OA patients with the rs8065080 poly-morphism experienced altered pain perception. The research team found that patients with asymptomatic knee OA were more likely to carry the rs8065080 gene than patients with painful joints [37]. This observation indicates that OA patients with normal functioning TRPV1 channels have an increased risk of joint pain and re-affirms the potential involvement of TRPV1 in OA pain perception.

Conclusion

While the hurdle of treating arthritis pain effectively still remains, great leaps are being made in our understanding of the neurophysiological processes responsible for the generation of joint pain. New targets are being discovered continually, while the mechanisms behind known pathways are being further defined and refined. Targeting one specific receptor or ion channel is unlikely to be the solution to normalizing joint pain, but rather a polypharmacy approach is indicated in which various mediators are used in combination during specific phases of the disease. Unravelling the functional circuitry at each level of the pain pathway will also improve our knowledge of how joint pain is generated. For example, identifying the peripheral mediators of joint pain will allow us to control nociception within the joint itself and likely avoid the central side effects of systemically-administered pharamcotherapeutics.

FACETOGENIC PAIN

facetogenic neuropathic, osteoarthritis and headaches pain el paso tx.
FACET SYNDROME & FACETOGENIC PAIN
  • Facet syndrome is an articular disorder related to the lumbar facet joints and their innervations, and produces both local and radiating facetogenic pain.
  • Excessive rotation, extension, or flexion of the spine (repeated overuse) can result in degenerative changes to the cartilage of the joint and may involve degenerative changes to other structures including the intervertebral disc

facetogenic neuropathic, osteoarthritis and headaches pain el paso tx.

CERVICAL FACET SYNDROME & FACETOGENIC PAIN

  • Axial neck pain (rarely radiating past the shoulders), most common unilaterally
  • Pain with and/or limitation of extension and rotation
  • Tenderness upon palpation
  • Radiating facetogenic pain locally or into the shoulders or upper back, and rarely radiate in the front or down an arm or into the fingers as a herniated disc might.

facetogenic neuropathic, osteoarthritis and headaches pain el paso tx.

LUMBAR FACET SYNDROME & FACETOGENIC PAIN

  • Pain or tenderness in lower back.
  • Local tenderness/stiffness alongside the spine in the lower back.
  • Pain, stiffness or difficulty with certain movements (such as standing up straight or getting up from a chair.
  • Pain upon hyperextension
  • Referred pain from upper lumbar facet joints can extend into the flank, hip and upper lateral thigh
  • Referred pain from lower lumbar facet joints can penetrate deep into the thigh, laterally and/or posteriorly
  • L4-L5 and L5-S1 facet joints can refer pain extending into the distal lateral leg, and in rare instances to the foot

facetogenic neuropathic, osteoarthritis and headaches pain el paso tx.

EVIDENCE-BASED MEDICINE

Evidence-based Interventional Pain Medicine according to Clinical Diagnoses

12. Pain Originating from the Lumbar Facet Joints

Abstract

Although the existence of a “facet syndrome” had long been questioned, it is now generally accepted as a clinical entity. Depending on the diagnostic criteria, the zygapophysial joints account for between 5% and 15% of cases of chronic, axial low back pain. Most commonly, facetogenic pain is the result of repetitive stress and/or cumulative low level trauma, leading to inflammation and stretching of the joint capsule. The most frequent complaint is axial low back pain with referred pain perceived in the flank, hip, and thigh. No physical examination findings are pathognomonic for diagnosis. The strongest indicator for lumbar facetogenic pain is pain reduction after anesthetic blocks of the rami mediales (medial branches) of the rami dorsales that innervate the facet joints. Because false-positive and, possibly, false negative results may occur, results must be interpreted carefully. In patients with injection-confirmed zygapophysial joint pain, procedural interventions can be undertaken in the context of a multidisciplinary, multimodal treatment regimen that includes pharmacotherapy, physical therapy and regular exercise, and, if indicated, psychotherapy. Currently, the “gold standard” for treating facetogenic pain is radio frequency treatment (1 B+). The evidence supporting intra-articular corticosteroids is limited; hence, this should be reserved for those individuals who do not respond to radio frequency treatment (2 B1).

Facetogenic Pain emanating from the lumbar facet joints is a common cause of low back pain in the adult population. Golthwaite was the first to describe the syndrome in 1911, and Ghormley is generally credited with coining the term “facet syndrome” in 1933. Facetogenic pain is defined as pain that arises from any structure that is part of the facet joints, including the fibrous capsule, synovial membrane, hyaline cartilage, and bone.3–5

More commonly, it is the result of repetitive stress and/or cumulative low-level trauma. This leads to inflammation, which can cause the facet joint to be filled with fluid and swell, which in turn results in stretching of the joint capsule and subsequent pain generation.27 Inflammatory changes around the facet joint can also irritate the spinal nerve via foraminal narrowing, resulting in sciatica. In addition, Igarashi et al.28 found that inflammatory cytokines released through the ventral joint capsule in patients with zygapophysial joint degeneration may be partially responsible for the neuropathic symptoms in individuals with spinal stenosis. Predisposing factors for zygapophysial joint pain include spondylolisthesis/lysis, degenerative disc disease, and advanced age.5

I.C ADDITIONAL TESTS

The prevalence rate of pathological changes in the facet joints on radiological examination depends on the mean age of the subjects, the radiological technique used, and the definition of “abnormality.” Degenerative facet joints can be best visualized via computed tomography (CT) examination.49

NEUROPATHIC PAIN

facetogenic neuropathic, osteoarthritis and headaches pain el paso tx.

  • Pain initiated or caused by a primary lesion or dysfunction in the somatosensory nervous system.
  • Neuropathic pain is usually chronic, difficult to treat and often resistant to standard analgesic management.
Abstract

Neuropathic pain is caused by a lesion or disease of the somatosensory system, including peripheral fibres (Aβ, Aδ and C fibres) and central neurons, and affects 7–10% of the general population. Multiple causes of neuropathic pain have been described and its incidence is likely to increase owing to the ageing global population, increased incidence of diabetes mellitus and improved survival from cancer after chemotherapy. Indeed, imbalances between excitatory and inhibitory somatosensory signalling, alterations in ion channels and variability in the way that pain messages are modulated in the central nervous system all have been implicated in neuropathic pain. The burden of chronic neuropathic pain seems to be related to the complexity of neuropathic symptoms, poor outcomes and difficult treatment decisions. Importantly, quality of life is impaired in patients with neuropathic pain owing to increased drug prescriptions and visits to health care providers, as well as the morbidity from the pain itself and the inciting disease. Despite challenges, progress in the understanding of the pathophysiology of neuropathic pain is spurring the development of new diagnostic procedures and personalized interventions, which emphasize the need for a multidisciplinary approach to the management of neuropathic pain.

PATHOGENESIS OF NEUROPATHIC PAIN

  • PERIPHERAL MECHANISMS
  • After a peripheral nerve lesion, neurons become more sensitive and develop abnormal excitability and elevated sensitivity to stimulation
  • This is known as…Peripheral Sensitization!

facetogenic neuropathic, osteoarthritis and headaches pain el paso tx.

  • CENTRAL MECHANISMS
  • As a consequence of ongoing spontaneous activity arising in the periphery, neurons develop an increased background activity, enlarged receptive fields and increased responses to afferent impulses, including normal tactile stimuli
    This is known as…Central Sensitization!

facetogenic neuropathic, osteoarthritis and headaches pain el paso tx.

facetogenic neuropathic, osteoarthritis and headaches pain el paso tx.

Chronic neuropathic pain is more frequent in women (8% versus 5.7% in men) and in patients >50 years of age (8.9% versus 5.6% in those <49 years of age), and most commonly affects the lower back and lower limbs, neck and upper limbs24. Lumbar and cervical painful radiculopathies are probably the most frequent cause of chronic neuropathic pain. Consistent with these data, a survey of >12,000 patients with chronic pain with both nociceptive and neuropathic pain types, referred to pain specialists in Germany, revealed that 40% of all patients experience at least some characteristics of neuropathic pain (such as burning sensations, numbness and tingling); patients with chronic back pain and radiculopathy were particularly affected25.

facetogenic neuropathic, osteoarthritis and headaches pain el paso tx.

The contribution of clinical neurophysiology to the comprehension of the tension-type headache mechanisms.

Abstract

So far, clinical neurophysiological studies on tension-type headache (TTH) have been conducted with two main purposes: (1) to establish whether some neurophysiological parameters may act as markers of TTH, and (2) to investigate the physiopathology of TTH. With regard to the first point, the present results are disappointing, since some abnormalities found in TTH patients may be frequently observed also in migraineurs. On the other hand, clinical neurophysiology has played an important role in the debate about the pathogenesis of TTH. Studies on the exteroceptive suppression of the temporalis muscle contraction have detected a dysfunction of the brainstem excitability and of its suprasegmental control. A similar conclusion has been reached by using the trigeminocervical reflexes, whose abnormalities in TTH have suggested a reduced inhibitory activity of brainstem interneurons, reflecting abnormal endogenous pain control mechanisms. It is interesting that the neural excitability abnormality in TTH seems to be a generalized phenomenon, not limited to the cranial districts. Defective DNIC-like mechanisms have indeed been evidenced also in somatic districts by nociceptive flexion reflex studies. Unfortunately, most neurophysiological studies on TTH are marred by serious methodological flaws, which should be avoided in future researches, in order to better clarify the TTH mechanisms.

facetogenic neuropathic, osteoarthritis and headaches pain el paso tx.

facetogenic neuropathic, osteoarthritis and headaches pain el paso tx.

facetogenic neuropathic, osteoarthritis and headaches pain el paso tx.

facetogenic neuropathic, osteoarthritis and headaches pain el paso tx.

facetogenic neuropathic, osteoarthritis and headaches pain el paso tx.

References:

Neurophysiology of arthritis pain. McDougall JJ1, Linton P.

https://www.researchgate.net/publication/232231610_Neurophysiology_of_Arthritis_Pain

Pain originating from the lumbar facet joints. van Kleef M1, Vanelderen P, Cohen SP, Lataster A, Van Zundert J, Mekhail N.

Neuropathic pain Luana Colloca,1 Taylor Ludman,1 Didier Bouhassira,2 Ralf Baron,3 Anthony H. Dickenson,4 David Yarnitsky,5Roy Freeman,6 Andrea Truini,7 Nadine Attal,8 Nanna B. Finnerup,9 Christopher Eccleston,10,11 Eija Kalso,12David L. Bennett,13 Robert H. Dworkin,14 and Srinivasa N. Raja15

The contribution of clinical neurophysiology to the comprehension of the tension-type headache mechanisms. Rossi P1, Vollono C, Valeriani M, Sandrini G.

Biomarkers And Pain Assessment Tools

Biomarkers And Pain Assessment Tools

Doctors define chronic pain, as any pain that lasts for 3 to 6 months or more. The pain effects an individual’s mental health and day to day life. Pain comes from a series of messages that run through the nervous system. Depression seems to follow pain. It causes severe symptoms that affect how an individual feels, thinks, and how the handle daily activities, i.e. sleeping, eating and working. Chiropractor, Dr. Alex Jimenez delves into potential biomarkers that can help in finding and treating the root causes of pain and chronic pain.

  • The first step in successful pain management is a comprehensive biopsychosocial assessment.
  • The extent of organic pathology may not be accurately reflected in the pain experience.
  • The initial assessment can be used to identify areas that require more in-depth evaluation.
  • Many validated self-report tools are available to assess the impact of chronic pain.

Assessment Of Patients With Chronic Pain

Chronic pain is a public health concern affecting 20–30% of the population of Western countries. Although there have been many scientific advances in the understanding of the neurophysiology of pain, precisely assessing and diagnosing a patient’s chronic pain problem is not straightforward or well-defined. How chronic pain is conceptualized influences how pain is evaluated and the factors considered when making a chronic pain diagnosis. There is no one-to-one relationship between the amount or type of organic pathology and pain intensity, but instead, the chronic pain experience is shaped by a myriad of biomedical, psychosocial (e.g. patients’ beliefs, expectations, and mood), and behavioral factors (e.g. context, responses by significant others). Assessing each of these three domains through a comprehensive evaluation of the person with chronic pain is essential for treatment decisions and to facilitate optimal outcomes. This evaluation should include a thorough patient history and medical evaluation and a brief screening interview where the patient’s behavior can be observed. Further assessment to address questions identified during the initial evaluation will guide decisions as to what additional assessments, if any, may be appropriate. Standardized self-reported instruments to evaluate the patient’s pain intensity, functional abilities, beliefs and expectations, and emotional distress are available, and can be administered by the physician, or a referral for in depth evaluation can be made to assist in treatment planning.

Pain is an extremely prevalent symptom. Chronic pain alone is estimated to affect 30% of the adult population of the USA, upwards of 100 million adults.1

Despite the soaring cost of treating people with chronic pain, relief for many remains elusive and complete elimination of pain is rare. Although there have been substantial advances in the knowledge of the neurophysiology of pain, along with the development of potent analgesic medications and other innovative medical and surgical interventions, on average the amount of pain reduction by available procedures is 30–40% and this occurs in fewer than one-half of treated patients.

The way we think about pain influences the way in which we go evaluate pain. Assessment begins with history and physical examination, followed, by laboratory tests and diagnostic imaging procedures in an attempt to identify and/or confirm the presence of any underlying pathology causing the symptom/s or the pain generator.

In the absence of identifiable organic pathology, the healthcare provider may assume that the report of symptoms stems from psychological factors and may request a psychological evaluation to detect the emotional factors underlying the patient’s report. There is duality where the report of symptoms are attributed to either somatic or psychogenic mechanisms.

As an example, the organic bases for some of the most common and recurring acute (e.g. headache)3 and chronic [e.g. back pain, fibromyalgia (FM)] pain problems are largely unknown,4,5 while on the other hand, asymptomatic individuals may have structural abnormalities such as herniated discs that would explain pain if it were present.6,7 There is a lacking in adequate explanations for patients with no identified organic pathology who report severe pain and pain-free individuals with significant, objective pathology.

Chronic pain affects more than just the individual patient, but also his or her significant others (partners, relatives, employers and co-workers and friends), making appropriate treatment essential. Satisfactory treatment can only come from comprehensive assessment of the biological aetiology of the pain in conjunction with the patient’s specific psychosocial and behavioral presentation, including their emotional state (e.g. anxiety, depression, and anger), perception and understanding of symptoms, and reactions to those symptoms by significant others.8,9 A key premise is that multiple factors influence the symptoms and functional limitations of individuals with chronic pain. Therefore, a comprehensive assessment is needed that addresses biomedical, psychosocial, and behavioral domains, as each contributes to chronic pain and related disability.10,11

Comprehensive Assessment Of An Individual With Chronic Pain

Turk and Meichenbaum12 suggested that three central questions should guide assessment of people who report pain:
  1. What is the extent of the patient’s disease or injury (physical impairment)?
  2. What is the magnitude of the illness? That is, to what extent is the patient suffering, disabled, and unable to enjoy usual activities?
  3. Does the individual’s behavior seem appropriate to the disease or injury, or is there any evidence of symptom amplification for any of a variety of psychological or social reasons (e.g. benefits such as positive attention, mood-altering medications, financial compensation)?

To answer these questions, information should be gathered from the patient by history and physical examination, in combination with a clinical interview, and through standardized assessment instruments. Healthcare providers need to seek any cause(s) of pain through physical examination and diagnostic tests while concomitantly assessing the patient’s mood, fears, expectancies, coping efforts, resources, responses of significant others, and the impact of pain on the patients’ lives.11 In short, the healthcare provider must evaluate the ‘whole person’ and not just the pain.

The general goals of the history and medical evaluation are to:

(i) determine the necessity of additional diagnostic testing

(ii) determine if medical data can explain the patient’s symptoms, symptom severity, and functional limitations

(iii) make a medical diagnosis

(iv) evaluate the availability of appropriate treatment

(v) establish the objectives of treatment

(vi) determine the appropriate course for symptom management if a complete cure is not possible.

Significant numbers of patients that report chronic pain demonstrate no physical pathology using plain radiographs, computed axial tomography scans, or electromyography (an extensive literature is available on physical assessment, radiographic and laboratory assessment procedures to determine the physical basis of pain),17 making a precise pathological diagnosis difficult or impossible.

Despite these limitations, the patient’s history and physical examination remain the basis of medical diagnosis, can provide a safeguard against over-interpreting findings from diagnostic imaging that are largely confirmatory, and can be used to guide the direction of further evaluation efforts.

biomarkers el paso tx.

In addition, patients with chronic pain problems often consume a variety of medications.18 It is important to discuss a patient’s current medications during the interview, as many pain medications are associated with side-effects that may cause or mimic emotional distress.19 Healthcare providers should not only be familiar with medications used for chronic pain, but also with side-effects from these medications that result in fatigue, sleep difficulties, and mood changes to avoid misdiagnosis of depression.

The use of daily diaries is believed to be more accurate as they are based on real-time rather than recall. Patients may be asked to maintain regular diaries of pain intensity with ratings recorded several times each day (e.g. meals and bedtime) for several days or weeks and multiple pain ratings can be averaged across time.

One problem noted with the use of paper-and-pencil diaries is that patients may not follow the instruction to provide ratings at specified intervals. Rather, patients may complete diaries in advance (‘fill forward’) or shortly before seeing a clinician (‘fill backward’),24 undermining the putative validity of diaries. Electronic diaries have gained acceptance in some research studies to avoid these problems.

Research has demonstrated the importance of assessing overall health-related quality of life (HRQOL) in chronic pain patients in addition to function.31,32 There are a number of well established, psychometrically supported HRQOL measures [Medical Outcomes Study Short-Form Health Survey (SF-36)],33 general measures of physical functioning [e.g. Pain Disability Index (PDI)],34 and disease-specific measures [e.g. Western Ontario MacMaster Osteoarthritis Index (WOMAC);35 Roland-Morris Back Pain Disability Questionnaire (RDQ)]36 to assess function and quality of life.

Disease-specific measures are designed to evaluate the impact of a specific condition (e.g. pain and stiffness in people with osteoarthritis), whereas generic measures make it possible to compare physical functioning associated with a given disorder and its treatment with that of various other conditions. Specific effects of a disorder may not be detected when using a generic measure; therefore, disease-specific measures may be more likely to reveal clinically important improvement or deterioration in specific functions as a result of treatment. General measures of functioning may be useful to compare patients with a diversity of painful conditions. The combined use of disease-specific and generic measures facilitates the achievement of both objectives.

The presence of emotional distress in people with chronic pain presents a challenge when assessing symptoms such as fatigue, reduced activity level, decreased libido, appetite change, sleep disturbance, weight gain or loss, and memory and concentration deficits, as these symptoms can be the result of pain, emotional distress, or treatment medications prescribed to control pain.

Instruments have been developed specifically for pain patients to assess psychological distress, the impact of pain on patients’ lives, feeling of control, coping behaviors, and attitudes about disease, pain, and healthcare providers.17

For example, the Beck Depression Inventory (BDI)39 and the Profile of Mood States (POMS)40 are psychometrically sound for assessing symptoms of depressed mood, emotional distress, and mood disturbance, and have been recommended to be used in all clinical trials of chronic pain;41 however, the scores must be interpreted with caution and the criteria for levels of emotional distress may need to be modified to prevent false positives.42

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Lab Biomarkers For Pain

Biomarkers are biological characteristics that can be used to indicate health or disease. This paper reviews studies on biomarkers of low back pain (LBP) in human subjects. LBP is the leading cause of disability, caused by various spine-related disorders, including intervertebral disc degeneration, disc herniation, spinal stenosis, and facet arthritis. The focus of these studies is inflammatory mediators, because inflammation contributes to the pathogenesis of disc degeneration and associated pain mechanisms. Increasingly, studies suggest that the presence of inflammatory mediators can be measured systemically in the blood. These biomarkers may serve as novel tools for directing patient care. Currently, patient response to treatment is unpredictable with a significant rate of recurrence, and, while surgical treatments may provide anatomical correction and pain relief, they are invasive and costly. The review covers studies performed on populations with specific diagnoses and undefined origins of LBP. Since the natural history of LBP is progressive, the temporal nature of studies is categorized by duration of symptomology/disease. Related studies on changes in biomarkers with treatment are also reviewed. Ultimately, diagnostic biomarkers of LBP and spinal degeneration have the potential to shepherd an era of individualized spine medicine for personalized therapeutics in the treatment of LBP.

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Biomarkers For Chronic Neuropathic Pain & Potential Application In Spinal Cord Stimulation

This review was focused on understanding which substances inside the human body increase and decrease with increasing neuropathic pain. We reviewed various studies, and saw correlations between neuropathic pain and components of the immune system (this system defends the body against diseases and infections). Our findings will especially be useful for understanding ways to reduce or eliminate the discomfort, chronic neuropathic pain brings with it. Spinal cord stimulation (SCS) procedure is one of the few fairly efficient remedial treatments for pain. A follow-up study will apply our findings from this review to SCS, in order to understand the mechanism, and further optimize efficaciousness.

Pro-inflammatory cytokines such as IL-1β, IL-6, IL-2, IL-33, CCL3, CXCL1, CCR5, and TNF-α, have been found to play significant roles in the amplification of chronic pain states.

After review of various studies relating to pain biomarkers, we found that serum levels of pro-inflammatory cytokines and chemokines, such as IL-1β, IL-6, IL-2, IL-33, CCL3, CXCL1, CCR5, and TNF-α, were significantly up-regulated during chronic pain experience. On the other hand, anti-inflammatory cytokines such as IL-10 and IL-4 were found to show significant down-regulation during chronic pain state.

Biomarkers For Depression

A plethora of research has implicated hundreds of putative biomarkers for depression, but has not yet fully elucidated their roles in depressive illness or established what is abnormal in which patients and how biologic information can be used to enhance diagnosis, treatment and prognosis. This lack of progress is partially due to the nature and heterogeneity of depression, in conjunction with methodological heterogeneity within the research literature and the large array of biomarkers with potential, the expression of which often varies according to many factors. We review the available literature, which indicates that markers involved in inflammatory, neurotrophic and metabolic processes, as well as neurotransmitter and neuroendocrine system components, represent highly promising candidates. These may be measured through genetic and epigenetic, transcriptomic and proteomic, metabolomic and neuroimaging assessments. The use of novel approaches and systematic research programs is now required to determine whether, and which, biomarkers can be used to predict response to treatment, stratify patients to specific treatments and develop targets for new interventions. We conclude that there is much promise for reducing the burden of depression through further developing and expanding these research avenues.

biomarkers el paso tx.References:

  • Assessment of patients with chronic pain E. J. Dansiet and D. C. Turk*t 

  • Inflammatory biomarkers of low back pain and disc degeneration: a review.
    Khan AN1, Jacobsen HE2, Khan J1, Filippi CG3, Levine M3, Lehman RA Jr2,4, Riew KD2,4, Lenke LG2,4, Chahine NO2,5.
  • Biomarkers for Chronic Neuropathic Pain and their Potential Application in Spinal Cord Stimulation: A Review
    Chibueze D. Nwagwu,1 Christina Sarris, M.D.,3 Yuan-Xiang Tao, Ph.D., M.D.,2 and Antonios Mammis, M.D.1,2
  • Biomarkers for depression: recent insights, current challenges and future prospects. Strawbridge R1, Young AH1,2, Cleare AJ1,2.
Safety and Side Effects of Cannabidiol

Safety and Side Effects of Cannabidiol

Cannabidiol is a compound in the Cannabis sativa plant, also known as marijuana. More than 80 chemicals, called cannabinoids, have been identified in the Cannabis sativa plant. Even though delta-9-tetrahydrocannabinol, or THC, is the major active ingredient, cannabidiol constitutes about 40 percent of cannabis extracts and has been analyzed for many distinct uses. According to the U.S. Food and Drug Administration, or the FDA, because cannabidiol was analyzed as a new drug, products containing cannabidiol are not defined as dietary supplements. But there are still products labeled as dietary supplements available on the marketplace which contain cannabidiol.

 

Cannabidiol has antipsychotic results. The exact cause for these effects isn’t clear. However, cannabidiol appears to protect against the breakdown of a chemical in the brain that affects pain, mood, and mental function. Preventing the breakdown of this compound and raising its levels in the blood seems to decrease psychotic symptoms related to conditions such as schizophrenia. Cannabidiol may also block some of the untoward effects of delta-9-tetrahydrocannabinol, or THC. Additionally, cannabidiol appears to decrease pain and anxiety. The purpose of the following article is to demonstrate an update on the safety and side effects of cannabidiol involving clinical data and relevant animal studies.

 

An Update on Safety and Side Effects of Cannabidiol: A Review of Clinical Data and Relevant Animal Studies

 

Abstract

 

  • Introduction: This literature survey aims to extend the comprehensive survey performed by Bergamaschi et al. in 2011 on cannabidiol (CBD) safety and side effects. Apart from updating the literature, this article focuses on clinical studies and CBD potential interactions with other drugs.
  • Results: In general, the often described favorable safety profile of CBD in humans was confirmed and extended by the reviewed research. The majority of studies were performed for treatment of epilepsy and psychotic disorders. Here, the most commonly reported side effects were tiredness, diarrhea, and changes of appetite/weight. In comparison with other drugs, used for the treatment of these medical conditions, CBD has a better side effect profile. This could improve patients’ compliance and adherence to treatment. CBD is often used as adjunct therapy. Therefore, more clinical research is warranted on CBD action on hepatic enzymes, drug transporters, and interactions with other drugs and to see if this mainly leads to positive or negative effects, for example, reducing the needed clobazam doses in epilepsy and therefore clobazam’s side effects.
  • Conclusion: This review also illustrates that some important toxicological parameters are yet to be studied, for example, if CBD has an effect on hormones. Additionally, more clinical trials with a greater number of participants and longer chronic CBD administration are still lacking.
  • Keywords: cannabidiol, cannabinoids, medical uses, safety, side effects, toxicity

 

Introduction

 

Since several years, other pharmacologically relevant constituents of the Cannabis plant, apart from Δ9-THC, have come into the focus of research and legislation. The most prominent of those is cannabidiol (CBD). In contrast to Δ9-THC, it is nonintoxicating, but exerts a number of beneficial pharmacological effects. For instance, it is anxiolytic, anti-inflammatory, antiemetic, and antipsychotic. Moreover, neuroprotective properties have been shown.1,2 Consequently, it could be used at high doses for the treatment of a variety of conditions ranging in psychiatric disorders such as schizophrenia and dementia, as well as diabetes and nausea.1,2

 

At lower doses, it has physiological effects that promote and maintain health, including antioxidative, anti-inflammatory, and neuroprotection effects. For instance, CBD is more effective than vitamin C and E as a neuroprotective antioxidant and can ameliorate skin conditions such as acne.3,4

 

The comprehensive review of 132 original studies by Bergamaschi et al. describes the safety profile of CBD, mentioning several properties: catalepsy is not induced and physiological parameters are not altered (heart rate, blood pressure, and body temperature). Moreover, psychological and psychomotor functions are not adversely affected. The same holds true for gastrointestinal transit, food intake, and absence of toxicity for nontransformed cells. Chronic use and high doses of up to 1500 mg per day have been repeatedly shown to be well tolerated by humans.1

 

Nonetheless, some side effects have been reported for CBD, but mainly in vitro or in animal studies. They include alterations of cell viability, reduced fertilization capacity, and inhibition of hepatic drug metabolism and drug transporters (e.g., p-glycoprotein).1 Consequently, more human studies have to be conducted to see if these effects also occur in humans. In these studies, a large enough number of subjects have to be enrolled to analyze long-term safety aspects and CBD possible interactions with other substances.

 

This review will build on the clinical studies mentioned by Bergamaschi et al. and will update their survey with new studies published until September 2016.

 

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Dr. Alex Jimenez’s Insight

Cannabidiol, or CBD, is a cannabis compound which is believed to have significant health benefits and can counteract the psychoactivity of THC. Because CBD is non-psychoactive or less psychoactive than THC-dominant strains, it has become an appealing treatment option for patients experiencing chronic pain, inflammation, anxiety, seizures, psychosis and other conditions without the common side effects. associated with THC. Numerous research studies have been conducted to demonstrate evidence on the health benefits of cannabidiol, or CBD, on the human body.

 

Relevant Preclinical Studies

 

Before we discuss relevant animal research on CBD possible effects on various parameters, several important differences between route of administration and pharmacokinetics between human and animal studies have to be mentioned. First, CBD has been studied in humans using oral administration or inhalation. Administration in rodents often occures either via intraperitoneal injection or via the oral route. Second, the plasma levels reached via oral administration in rodents and humans can differ. Both these observations can lead to differing active blood concentrations of CBD.1,5,6

 

In addition, it is possible that CBD targets differ between humans and animals. Therefore, the same blood concentration might still lead to different effects. Even if the targets, to which CBD binds, are the same in both studied animals and humans, for example, the affinity or duration of CBD binding to its targets might differ and consequently alter its effects.

 

The following study, which showed a positive effect of CBD on obsessive compulsive behavior in mice and reported no side effects, exemplifies the existing pharmacokinetic differences.5 When mice and humans are given the same CBD dose, more of the compound becomes available in the mouse organism. This higher bioavailability, in turn, can cause larger CBD effects.

 

Deiana et al. administered 120 mg/kg CBD either orally or intraperitoneally and measured peak plasma levels.5 The group of mice, which received oral CBD, had plasma levels of 2.2 μg/ml CBD. In contrast, i.p. injections resulted in peak plasma levels of 14.3 μg/ml. Administering 10 mg/kg oral CBD to humans leads to blood levels of 0.01 μg/ml.6 This corresponds to human blood levels of 0.12 μg/ml, when 120 mg/kg CBD was given to humans. This calculation was performed assuming the pharmacokinetics of a hydrophilic compound, for simplicity’s sake. We are aware that the actual levels of the lipophilic CBD will vary.

 

A second caveat of preclinical studies is that supraphysiological concentrations of compounds are often used. This means that the observed effects, for instance, are not caused by a specific binding of CBD to one of its receptors but are due to unspecific binding following the high compound concentration, which can inactivate the receptor or transporter.

 

The following example and calculations will demonstrate this. In vitro studies have shown that CBD inhibits the ABC transporters P-gp (P glycoprotein also referred to as ATP-binding cassette subfamily B member 1=ABCB1; 3–100 μM CBD) and Bcrp (Breast Cancer Resistance Protein; also referred to as ABCG2=ATP-binding cassette subfamily G member 2).7 After 3 days, the P-gp protein expression was altered in leukemia cells. This can have several implications because various anticancer drugs also bind to these membrane-bound, energy-dependent efflux transporters.1 The used CBD concentrations are supraphysiological, however, 3 μM CBD approximately corresponds to plasma concentrations of 1 μg/ml. On the contrary, a 700 mg CBD oral dose reached a plasma level of 10 ng/ml.6 This means that to reach a 1 μg/ml plasma concentration, one would need to administer considerably higher doses of oral CBD. The highest ever applied CBD dose was 1500 mg.1 Consequently, more research is warranted, where the CBD effect on ABC transporters is analyzed using CBD concentrations of, for example, 0.03–0.06 μM. The rationale behind suggesting these concentrations is that studies summarized by Bih et al. on CBD effect on ABCC1 and ABCG2 in SF9 human cells showed that a CBD concentration of 0.08 μM elicited the first effect.7

 

Using the pharmacokinetic relationships mentioned above, one would need to administer an oral CBD dose of 2100 mg CBD to affect ABCC1 and ABCG2. We used 10 ng/ml for these calculations and the ones in Table 1,6,8 based on a 6-week trial using a daily oral administration of 700 mg CBD, leading to mean plasma levels of 6–11 ng/ml, which reflects the most realistic scenario of CBD administration in patients.6 That these levels seem to be reproducible, and that chronic CBD administration does not lead to elevated mean blood concentrations, was shown by another study. A single dose of 600 mg led to reduced anxiety and mean CBD blood concentrations of 4.7–17 ng/ml.9

 

Table 1 Inhibition of Human Metabolic Enzymes

 

It also seems warranted to assume that the mean plasma concentration exerts the total of observed CBD effects, compared to using peak plasma levels, which only prevail for a short amount of time. This is not withstanding, that a recent study measured Cmax values for CBD of 221 ng/ml, 3 h after administration of 1 mg/kg fentanyl concomitantly with a single oral dose of 800 mg CBD.10

 

CBD-Drug Interactions

 

Cytochrome P450-complex enzymes. This paragraph describes CBD interaction with general (drug)-metabolizing enzymes, such as those belonging to the cytochrome P450 family. This might have an effect for coadministration of CBD with other drugs.7 For instance, CBD is metabolized, among others, via the CYP3A4 enzyme. Various drugs such as ketoconazol, itraconazol, ritonavir, and clarithromycin inhibit this enzyme.11 This leads to slower CBD degradation and can consequently lead to higher CBD doses that are longer pharmaceutically active. In contrast, phenobarbital, rifampicin, carbamazepine, and phenytoin induce CYP3A4, causing reduced CBD bioavailability.11 Approximately 60% of clinically prescribed drugs are metabolized via CYP3A4.1 Table 1 shows an overview of the cytochrome inhibiting potential of CBD. It has to be pointed out though, that the in vitro studies used supraphysiological CBD concentrations.

 

Studies in mice have shown that CBD inactivates cytochrome P450 isozymes in the short term, but can induce them after repeated administration. This is similar to their induction by phenobarbital, thereby implying the 2b subfamily of isozymes.1 Another study showed this effect to be mediated by upregulation of mRNA for CYP3A, 2C, and 2B10, after repeated CBD administration.1

 

Hexobarbital is a CYP2C19 substrate, which is an enzyme that can be inhibited by CBD and can consequently increase hexobarbital availability in the organism.12,13 Studies also propose that this effect might be caused in vivo by one of CBD metabolites.14,15 Generally, the metabolite 6a-OH-CBD was already demonstrated to be an inducer of CYP2B10. Recorcinol was also found to be involved in CYP450 induction. The enzymes CYP3A and CYP2B10 were induced after prolonged CBD administration in mice livers, as well as for human CYP1A1 in vitro.14,15 On the contrary, CBD induces CYP1A1, which is responsible for degradation of cancerogenic substances such as benzopyrene. CYP1A1 can be found in the intestine and CBD-induced higher activity could therefore prevent absorption of cancerogenic substances into the bloodstream and thereby help to protect DNA.2

 

Effects on P-glycoprotein activity and other drug transporters. A recent study with P-gp, Bcrp, and P-gp/Bcrp knockout mice, where 10 mg/kg was injected subcutaneously, showed that CBD is not a substrate of these transporters itself. This means that they do not reduce CBD transport to the brain.16 This phenomenon also occurs with paracetamol and haloperidol, which both inhibit P-gp, but are not actively transported substrates. The same goes for gefitinib inhibition of Bcrp.

 

These proteins are also expressed at the blood–brain barrier, where they can pump out drugs such as risperidone. This is hypothesized to be a cause of treatment resistance.16 In addition, polymorphisms in these genes, making transport more efficient, have been implied in interindividual differences in pharmacoresistance.10 Moreover, the CBD metabolite 7-COOH CBD might be a potent anticonvulsant itself.14 It will be interesting to see whether it is a P-gp substrate and alters pharmacokinetics of coadministered P-gp-substrate drugs.

 

An in vitro study using three types of trophoblast cell lines and ex vivo placenta, perfused with 15 μM CBD, found BCRP inhibition leading to accumulation of xenobiotics in the fetal compartment.17 BCRP is expressed at the apical side of the syncytiotrophoblast and removes a wide variety of compounds forming a part of the placental barrier. Seventy-two hours of chronic incubation with 25 μM CBD also led to morphological changes in the cell lines, but not to a direct cytotoxic effect. In contrast, 1 μM CBD did not affect cell and placenta viability.17 The authors consider this effect cytostatic. Nicardipine was used as the BCRP substrate in the in vitro studies, where the Jar cell line showed the largest increase in BCRP expression correlating with the highest level of transport.17,and references therein

 

The ex vivo study used the antidiabetic drug and BCRP substrate glyburide.17 After 2 h of CBD perfusion, the largest difference between the CBD and the placebo placentas (n=8 each) was observed. CBD inhibition of the BCRP efflux function in the placental cotyledon warrants further research of coadministration of CBD with known BCRP substrates such as nitrofurantoin, cimetidine, and sulfasalazine. In this study, a dose–response curve should be established in male and female subjects (CBD absorption was shown to be higher in women) because the concentrations used here are usually not reached by oral or inhaled CBD administration. Nonetheless, CBD could accumulate in organs physiologically restricted via a blood barrier.17

 

Physiological Effects

 

CBD treatment of up to 14 days (3–30 mg/kg b.w. i.p.) did not affect blood pressure, heart rate, body temperature, glucose levels, pH, pCO2, pO2, hematocrit, K+ or Na+ levels, gastrointestinal transit, emesis, or rectal temperature in a study with rodents.1

 

Mice treated with 60 mg/kg b.w. CBD i.p. for 12 weeks (three times per week) did not show ataxia, kyphosis, generalized tremor, swaying gait, tail stiffness, changes in vocalization behavior or open-field physiological activity (urination, defecation).1

 

Neurological and Neurospychiatric Effects

 

Anxiety and depression. Some studies indicate that under certain circumstances, CBD acute anxiolytic effects in rats were reversed after repeated 14-day administration of CBD.2 However, this finding might depend on the used animal model of anxiety or depression. This is supported by a study, where CBD was administered in an acute and “chronic” (2 weeks) regimen, which measured anxiolytic/antidepressant effects, using behavioral and operative models (OBX=olfactory bulbectomy as model for depression).18 The only observed side effects were reduced sucrose preference, reduced food consumption and body weight in the nonoperated animals treated with CBD (50 mg/kg). Nonetheless, the behavioral tests (for OBX-induced hyperactivity and anhedonia related to depression and open field test for anxiety) in the CBD-treated OBX animals showed an improved emotional response. Using microdialysis, the researchers could also show elevated 5-HT and glutamate levels in the prefrontal cortex of OBX animals only. This area was previously described to be involved in maladaptive behavioral regulation in depressed patients and is a feature of the OBX animal model of depression. The fact that serotonin levels were only elevated in the OBX mice is similar to CBD differential action under physiological and pathological conditions.

 

A similar effect was previously described in anxiety experiments, where CBD proved to be only anxiolytic in subjects where stress had been induced before CBD administration. Elevated glutamate levels have been proposed to be responsible for ketamine’s fast antidepressant function and its dysregulation has been described in OBX mice and depressed patients. Chronic CBD treatment did not elicit behavioral changes in the nonoperated mice. In contrast, CBD was able to alleviate the affected functionality of 5HT1A receptors in limbic brain areas of OBX mice.18 and references therein.

 

Schiavon et al. cite three studies that used chronic CBD administration to demonstrate its anxiolytic effects in chronically stressed rats, which were mostly mediated via hippocampal neurogenesis.19 and references therein For instance, animals received daily i.p. injections of 5 mg/kg CBD. Applying a 5HT1A receptor antagonist in the DPAG (dorsal periaqueductal gray area), it was implied that CBD exerts its antipanic effects via these serotonin receptors. No adverse effects were reported in this study.

 

Psychosis and bipolar disorder. Various studies on CBD and psychosis have been conducted.20 For instance, an animal model of psychosis can be created in mice by using the NMDAR antagonist MK-801. The behavioral changes (tested with the prepulse inhibition [PPI] test) were concomitant with decreased mRNA expression of the NMDAR GluN1 subunit gene (GRN1) in the hippocampus, decreased parvalbumin expression (=a calcium-binding protein expressed in a subclass of GABAergic interneurons), and higher FosB/ΔFosB expression (=markers for neuronal activity). After 6 days of MK-801 treatment, various CBD doses were injected intraperitoneally (15, 30, 60 mg/kg) for 22 days. The two higher CBD doses had beneficial effects comparable to the atypical antipsychotic drug clozapine and also attenuated the MK-801 effects on the three markers mentioned above. The publication did not record any side effects.21

 

One of the theories trying to explain the etiology of bipolar disorder (BD) is that oxidative stress is crucial in its development. Valvassori et al. therefore used an animal model of amphetamine-induced hyperactivity to model one of the symptoms of mania. Rats were treated for 14 days with various CBD concentrations (15, 30, 60 mg/kg daily i.p.). Whereas CBD did not have an effect on locomotion, it did increase brain-derived neurotrophic factor (BDNF) levels and could protect against amphetamine-induced oxidative damage in proteins of the hippocampus and striatum. No adverse effects were recorded in this study.22

 

Another model for BD and schizophrenia is PPI of the startle reflex both in humans and animals, which is disrupted in these diseases. Peres et al., list five animal studies, where mostly 30 mg/kg CBD was administered and had a positive effect on PPI.20 Nonetheless, some inconsistencies in explaining CBD effects on PPI as model for BD exist. For example, CBD sometimes did not alter MK-801-induced PPI disruption, but disrupted PPI on its own.20 If this effect can be observed in future experiments, it could be considered to be a possible side effect.

 

Addiction. CBD, which is nonhedonic, can reduce heroin-seeking behavior after, for example, cue-induced reinstatement. This was shown in an animal heroin self-administration study, where mice received 5 mg/kg CBD i.p. injections. The observed effect lasted for 2 weeks after CBD administration and could normalize the changes seen after stimulus cue-induced heroin seeking (expression of AMPA, GluR1, and CB1R). In addition, the described study was able to replicate previous findings showing no CBD side effects on locomotor behavior.23

 

Neuroprotection and neurogenesis. There are various mechanisms underlying neuroprotection, for example, energy metabolism (whose alteration has been implied in several psychiatric disorders) and proper mitochondrial functioning.24 An early study from 1976 found no side effects and no effect of 0.3–300 μg/mg protein CBD after 1 h of incubation on mitochondrial monoamine oxidase activity in porcine brains.25 In hypoischemic newborn pigs, CBD elicited a neuroprotective effect, caused no side effects, and even led to beneficial effects on ventilatory, cardiac, and hemodynamic functions.26

 

A study comparing acute and chronic CBD administration in rats suggests an additional mechanism of CBD neuroprotection: Animals received i.p. CBD (15, 30, 60 mg/kg b.w.) or vehicle daily, for 14 days. Mitochondrial activity was measured in the striatum, hippocampus, and the prefrontal cortex.27 Acute and chronic CBD injections led to increased mitochondrial activity (complexes I-V) and creatine kinase, whereas no side effects were documented. Chronic CBD treatment and the higher CBD doses tended to affect more brain regions. The authors hypothesized that CBD changed the intracellular Ca2+ flux to cause these effects. Since the mitochondrial complexes I and II have been implied in various neurodegenerative diseases and also altered ROS (reactive oxygen species) levels, which have also been shown to be altered by CBD, this might be an additional mechanism of CBD-mediated neuroprotection.1,27

 

Interestingly, it has recently been shown that the higher ROS levels observed after CBD treatment were concomitant with higher mRNA and protein levels of heat shock proteins (HSPs). In healthy cells, this can be interpreted as a way to protect against the higher ROS levels resulting from more mitochondrial activity. In addition, it was shown that HSP inhibitors increase the CBD anticancer effect in vitro.28 This is in line with the studies described by Bergamaschi et al., which also imply ROS in CBD effect on (cancer) cell viability in addition to, for example, proapoptotic pathways such as via caspase-8/9 and inhibition of the procarcinogenic lipoxygenase pathway.1

 

Another publication studied the difference of acute and chronic administration of two doses of CBD in nonstressed mice on anxiety. Already an acute i.p. administration of 3 mg/kg was anxiolytic to a degree comparable to 20 mg/kg imipramine (an selective serotonin reuptake inhibitor [SSRI] commonly prescribed for anxiety and depression). Fifteen days of repeated i.p. administration of 3 mg/kg CBD also increased cell proliferation and neurogenesis (using three different markers) in the subventricular zone and the hippocampal dentate gyrus. Interestingly, the repeated administration of 30 mg/kg also led to anxiolytic effects. However, the higher dose caused a decrease in neurogenesis and cell proliferation, indicating dissociation of behavioral and proliferative effects of chronic CBD treatment. The study does not mention adverse effects.19

 

Immune System

 

Numerous studies show the CBD immunomodulatory role in various diseases such as multiple sclerosis, arthritis, and diabetes. These animal and human ex vivo studies have been reviewed extensively elsewhere, but studies with pure CBD are still lacking. Often combinations of THC and CBD were used. It would be especially interesting to study when CBD is proinflammatory and under which circumstances it is anti-inflammatory and whether this leads to side effects (Burstein, 2015: Table 1 shows a summary of its anti-inflammatory actions; McAllister et al. give an extensive overview in Table 1 of the interplay between CBD anticancer effects and inflammation signaling).29,30

 

In case of Alzheimer’s disease (AD), studies in mice and rats showed reduced amyloid beta neuroinflammation (linked to reduced interleukin [IL]-6 and microglial activation) after CBD treatment. This led to amelioration of learning effects in a pharmacological model of AD. The chronic study we want to describe in more detail here used a transgenic mouse model of AD, where 2.5-month-old mice were treated with either placebo or daily oral CBD doses of 20 mg/kg for 8 months (mice are relatively old at this point). CBD was able to prevent the development of a social recognition deficit in the AD transgenic mice.

 

Moreover, the elevated IL-1 beta and TNF alpha levels observed in the transgenic mice could be reduced to WT (wild-type) levels with CBD treatment. Using statistical analysis by analysis of variance, this was shown to be only a trend. This might have been caused by the high variation in the transgenic mouse group, though. Also, CBD increased cholesterol levels in WT mice but not in CBD-treated transgenic mice. This was probably due to already elevated cholesterol in the transgenic mice. The study observed no side effects.31 and references within

 

In nonobese diabetes-prone female mice (NOD), CBD was administered i.p. for 4 weeks (5 days a week) at a dose of 5 mg/kg per day. After CBD treatment was stopped, observation continued until the mice were 24 weeks old. CBD treatment lead to considerable reduction of diabetes development (32% developed glucosuria in the CBD group compared to 100% in untreated controls) and to more intact islet of Langerhans cells. CBD increased IL-10 levels, which is thought to act as an anti-inflammatory cytokine in this context. The IL-12 production of splenocytes was reduced in the CBD group and no side effects were recorded.32

 

After inducing arthritis in rats using Freund’s adjuvant, various CBD doses (0.6, 3.1, 6.2, or 62.3 mg/day) were applied daily in a gel for transdermal administration for 4 days. CBD reduced joint swelling, immune cell infiltration. thickening of the synovial membrane, and nociceptive sensitization/spontaneous pain in a dose-dependent manner, after four consecutive days of CBD treatment. Proinflammatory biomarkers were also reduced in a dose-dependent manner in the dorsal root ganglia (TNF alpha) and spinal cord (CGRP, OX42). No side effects were evident and exploratory behavior was not altered (in contrast to Δ9-THC, which caused hypolocomotion).33

 

Cell Migration

 

Embryogenesis. CBD was shown to be able to influence migratory behavior in cancer, which is also an important aspect of embryogenesis.1 For instance, it was recently shown that CBD inhibits Id-1. Helix-loop-helix Id proteins play a role in embryogenesis and normal development via regulation of cell differentiation. High Id1-levels were also found in breast, prostate, brain, and head and neck tumor cells, which were highly aggressive. In contrast, Id1 expression was low in noninvasive tumor cells. Id1 seems to influence the tumor cell phenotype by regulation of invasion, epithelial to mesenchymal transition, angiogenesis, and cell proliferation.34

 

There only seems to exist one study that could not show an adverse CBD effect on embryogenesis. An in vitro study could show that the development of two-cell embryos was not arrested at CBD concentrations of 6.4, 32, and 160 nM.35

 

Cancer. Various studies have been performed to study CBD anticancer effects. CBD anti-invasive actions seem to be mediated by its TRPV1 stimulation and its action on the CB receptors. Intraperitoneal application of 5 mg/kg b.w. CBD every 3 days for a total of 28 weeks, almost completely reduced the development of metastatic nodules caused by injection of human lung carcinoma cells (A549) in nude mice.36 This effect was mediated by upregulation of ICAM1 and TIMP1. This, in turn, was caused by upstream regulation of p38 and p42/44 MAPK pathways. The typical side effects of traditional anticancer medication, emesis, and collateral toxicity were not described in these studies. Consequently, CBD could be an alternative to other MMP1 inhibitors such as marimastat and prinomastat, which have shown disappointing clinical results due to these drugs’ adverse muscoskeletal effects.37,38

 

Two studies showed in various cell lines and in tumor-bearing mice that CBD was able to reduce tumor metastasis.34,39 Unfortunately, the in vivo study was only described in a conference abstract and no route of administration or CBD doses were mentioned.36 However, an earlier study used 0.1, 1.0, or 1.5 μmol/L CBD for 3 days in the aggressive breast cancer cells MDA-MB231. CBD downregulated Id1 at promoter level and reduced tumor aggressiveness.40

 

Another study used xenografts to study the proapoptotic effect of CBD, this time in LNCaP prostate carcinoma cells.36 In this 5-week study, 100 mg/kg CBD was administered daily i.p. Tumor volume was reduced by 60% and no adverse effects of treatment were described in the study. The authors assumed that the observed antitumor effects were mediated via TRPM8 together with ROS release and p53 activation.41 It has to be pointed out though, that xenograft studies only have limited predictive validity to results with humans. Moreover, to carry out these experiments, animals are often immunologically compromised, to avoid immunogenic reactions as a result to implantation of human cells into the animals, which in turn can also affect the results.42

 

Another approach was chosen by Aviello et al.43 They used the carcinogen azoxymethane to induce colon cancer in mice. Treatment occurred using IP injections of 1 or 5 mg/kg CBD, three times a week for 3 weeks (including 1 week before carcinogen administration). After 3 months, the number of aberrant crypt foci, polyps, and tumors was analyzed. The high CBD concentration led to a significant decrease in polyps and a return to near-normal levels of phosphorylated Akt (elevation caused by the carcinogen).42 No adverse effects were mentioned in the described study.43

 

Food Intake and Glycemic Effects

 

Animal studies summarized by Bergamaschi et al. showed inconclusive effects of CBD on food intake1: i.p. administration of 3–100 mg/kg b.w. had no effect on food intake in mice and rats. On the contrary, the induction of hyperphagia by CB1 and 5HT1A agonists in rats could be decreased with CBD (20 mg/kg b.w. i.p.). Chronic administration (14 days, 2.5 or 5 mg/kg i.p.) reduced the weight gain in rats. This effect could be inhibited by coadministration of a CB2R antagonist.1

 

The positive effects of CBD on hyperglycemia seem to be mainly mediated via CBD anti-inflammatory and antioxidant effects. For instance, in ob/ob mice (an animal model of obesity), 4-week treatment with 3 mg/kg (route of administration was not mentioned) increased the HDL-C concentration by 55% and reduced total cholesterol levels by more than 25%. In addition, treatment increased adiponectin and liver glycogen concentrations.44 and references therein.

 

Endocrine Effects

 

High CBD concentrations (1 mM) inhibited progesterone 17-hydroxylase, which creates precursors for sex steroid and glucocorticoid synthesis, whereas 100 μM CBD did not in an in vitro experiment with primary testis microsomes.45 Rats treated with 10 mg/kg i.p. b.w. CBD showed inhibition of testosterone oxidation in the liver.46

 

Genotoxicity and Mutagenicity

 

Jones et al. mention that 120 mg/kg CBD delivered intraperetonially to Wistar Kyoto rats showed no mutagenicity and genotoxicity based on personal communication with GW Pharmaceuticals47,48 These data are yet to be published. The 2012 study with an epilepsy mouse model could also show that CBD did not influence grip strength, which the study describes as a “putative test for functional neurotoxicity.”48

 

Motor function was also tested on a rotarod, which was also not affected by CBD administration. Static beam performance, as an indicator of sensorimotor coordination, showed more footslips in the CBD group, but CBD treatment did not interfere with the animals’ speed and ability to complete the test. Compared to other anticonvulsant drugs, this effect was minimal.48 Unfortunately, we could not find more studies solely focusing on genotoxicity by other research groups neither in animals nor in humans.

 

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Dr. Alex Jimenez’s Insight

Clinical and scientific research has attempted to show the effects of cannabidiol, or CBD, for the treatment of a wide range of conditions, including arthritis, diabetes, multiple sclerosis, chronic pain, schizophrenia, PTSD, depression, anxiety, infections, epilepsy, and many other neurological disorders. Evidence has also found that cannabidiol has neuroprotective and neurogenic effects and its anti-cancer properties are currently being investigated in many research studies. Further evidence has suggested that CBD can also be safe and effective even in higher doses, as recommended by a healthcare professional.

 

Acute Clinical Data

 

Bergamaschi et al. list an impressive number of acute and chronic studies in humans, showing CBD safety for a wide array of side effects.1 They also conclude from their survey, that none of the studies reported tolerance to CBD. Already in the 1970s, it was shown that oral CBD (15–160 mg), iv injection (5–30 mg), and inhalation of 0.15 mg/kg b.w. CBD did not lead to adverse effects. In addition, psychomotor function and psychological functions were not disturbed. Treatment with up to 600 mg CBD neither influenced physiological parameters (blood pressure, heart rate) nor performance on a verbal paired-associate learning test.1

 

Fasinu et al. created a table with an overview of clinical studies currently underway, registered in Clinical Trials. gov.49 In the following chapter, we highlight recent, acute clinical studies with CBD.

 

CBD-Drug Interactions

 

CBD can inhibit CYP2D6, which is also targeted by omeprazole and risperidone.2,14 There are also indications that CBD inhibits the hepatic enzyme CYP2C9, reducing the metabolization of warfarin and diclofenac.2,14 More clinical studies are needed, to check whether this interaction warrants an adaption of the used doses of the coadministered drugs.

 

The antibiotic rifampicin induces CYP3A4, leading to reduced CBD peak plasma concentrations.14 In contrast, the CYP3A4 inhibitor ketoconazole, an antifungal drug, almost doubles CBD peak plasma concentration. Interestingly, the CYP2C19 inhibitor omeprazole, used to treat gastroesophageal reflux, could not significantly affect the pharmacokinetics of CBD.14

 

A study, where a regimen of 6×100 mg CBD daily was coadministered with hexobarbital in 10 subjects, found that CBD increased the bioavailability and elimination half-time of the latter. Unfortunately, it was not mentioned whether this effect was mediated via the cytochrome P450 complex.16

 

Another aspect, which has not been thoroughly looked at, to our knowledge, is that several cytochrome isozymes are not only expressed in the liver but also in the brain. It might be interesting to research organ-specific differences in the level of CBD inhibition of various isozymes. Apart from altering the bioavailability in the overall plasma of the patient, this interaction might alter therapeutic outcomes on another level. Dopamine and tyramine are metabolized by CYP2D6, and neurosteroid metabolism also occurs via the isozymes of the CYP3A subgroup.50,51 Studying CBD interaction with neurovascular cytochrome P450 enzymes might also offer new mechanisms of action. It could be possible that CBD-mediated CYP2D6 inhibition increases dopamine levels in the brain, which could help to explain the positive CBD effects in addiction/withdrawal scenarios and might support its 5HT (=serotonin) elevating effect in depression.

 

Also, CBD can be a substrate of UDP glucuronosyltransferase.14 Whether this enzyme is indeed involved in the glucuronidation of CBD and also causes clinically relevant drug interactions in humans is yet to be determined in clinical studies. Generally, more human studies, which monitor CBD-drug interactions, are needed.

 

Physiological Effects

 

In a double-blind, placebo-controlled crossover study, CBD was coadministered with intravenous fentanyl to a total of 17 subjects.10 Blood samples were obtained before and after 400 mg CBD (previously demonstrated to decrease blood flow to (para)limbic areas related to drug craving) or 800 mg CBD pretreatment. This was followed by a single 0.5 (Session 1) or 1.0μg/kg (Session 2, after 1 week of first administration to allow for sufficient drug washout) intravenous fentanyl dose. Adverse effects and safety were evaluated with both forms of the Systematic Assessment for Treatment Emergent Events (SAFTEE). This extensive tool tests, for example, 78 adverse effects divided into 23 categories corresponding to organ systems or body parts. The SAFTEE outcomes were similar between groups. No respiratory depression or cardiovascular complications were recorded during any test session.

 

The results of the evaluation of pharmacokinetics, to see if interaction between the drugs occurred, were as follows. Peak CBD plasma concentrations of the 400 and 800 mg group were measured after 4 h in the first session (CBD administration 2 h after light breakfast). Peak urinary CBD and its metabolite concentrations occurred after 6 h in the low CBD group and after 4 h in the high CBD group. No effect was evident for urinary CBD and metabolite excretion except at the higher fentanyl dose, in which CBD clearance was reduced. Importantly, fentanyl coadministration did not produce respiratory depression or cardiovascular complications during the test sessions and CBD did not potentiate fentanyl’s effects. No correlation was found between CBD dose and plasma cortisol levels.

 

Various vital signs were also measured (blood pressure, respiratory/heart rate, oxygen saturation, EKG, respiratory function): CBD did not worsen the adverse effects (e.g., cardiovascular compromise, respiratory depression) of iv fentanyl. Coadministration was safe and well tolerated, paving the way to use CBD as a potential treatment for opioid addiction. The validated subjective measures scales Anxiety (visual analog scale [VAS]), PANAS (positive and negative subscores), and OVAS (specific opiate VAS) were administered across eight time points for each session without any significant main effects for CBD for any of the subjective effects on mood.10

 

A Dutch study compared subjective adverse effects of three different strains of medicinal cannabis, distributed via pharmacies, using VAS. “Visual analog scale is one of the most frequently used psychometric instruments to measure the extent and nature of subjective effects and adverse effects. The 12 adjectives used for this study were as follows: alertness, tranquility, confidence, dejection, dizziness, confusion/disorientation, fatigue, anxiety, irritability, appetite, creative stimulation, and sociability.” The high CBD strain contained the following concentrations: 6% Δ9-THC/7.5% CBD (n=25). This strain showed significantly lower levels of anxiety and dejection. Moreover, appetite increased less in the high CBD strain. The biggest observed adverse effect was “fatigue” with a score of 7 (out of 10), which did not differ between the three strains.52

 

Neurological and Neurospychiatric Effects

 

Anxiety. Forty-eight participants received subanxiolytic levels (32 mg) of CBD, either before or after the extinction phase in a double-blind, placebo-controlled design of a Pavlovian fear-conditioning experiment (recall with conditioned stimulus and context after 48 h and exposure to unconditioned stimulus after reinstatement). Skin conductance (=autonomic response to conditioning) and shock expectancy measures (=explicit aspects) of conditioned responding were recorded throughout. Among other scales, the Mood Rating Scale (MRS) and the Bond and Bodily Symptoms Scale were used to assess anxiety, current mood, and physical symptoms. “CBD given postextinction (active after consolidation phase) enhanced consolidation of extinction learning as assessed by shock expectancy.” Apart from the extinction-enhancing effects of CBD in human aversive conditioned memory, CBD showed a trend toward some protection against reinstatement of contextual memory. No side/adverse effects were reported.53

 

Psychosis. The review by Bergamaschi et al. mentions three acute human studies that have demonstrated the CBD antipsychotic effect without any adverse effects being observed. This holds especially true for the extrapyramidal motor side effects elicited by classical antipsychotic medication.1

 

Fifteen male, healthy subjects with minimal prior Δ9-THC exposure (<15 times) were tested for CBD affecting Δ9-THC propsychotic effects using functional magnetic resonance imaging (fMRI) and various questionnaires on three occasions, at 1-month intervals, following administration of 10 mg delta-9-Δ9-THC, 600 mg CBD, or placebo. Order of drug administration was pseudorandomized across subjects, so that an equal number of subjects received any of the drugs during the first, second, or third session in a double-blind, repeated-measures, within-subject design.54 No CBD effect on psychotic symptoms as measured with PANSS positive symptoms subscale, anxiety as indexed by the State Trait Anxiety Inventory (STAI) state, and Visual Analogue Mood Scale (VAMS) tranquilization or calming subscale, compared to the placebo group, was observed. The same is true for a verbal learning task (=behavioral performance of the verbal memory).

 

Moreover, pretreatment with CBD and subsequent Δ9-THC administration could reduce the latter’s psychotic and anxiety symptoms, as measured using a standardized scale. This effect was caused by opposite neural activation of relevant brain areas. In addition, no effects on peripheral cardiovascular measures such as heart rate and blood pressure were measured.54

 

A randomized, double-blind, crossover, placebo-controlled trial was conducted in 16 healthy nonanxious subjects using a within-subject design. Oral Δ9-THC=10 mg, CBD=600 mg, or placebo was administered in three consecutive sessions at 1-month intervals. The doses were selected to only evoke neurocognitive effects without causing severe toxic, physical, or psychiatric reactions. The 600 mg CBD corresponded to mean (standard deviation) whole blood levels of 0.36 (0.64), 1.62 (2.98), and 3.4 (6.42) ng/mL, 1, 2, and 3 h after administration, respectively.

 

Physiological measures and symptomatic effects were assessed before, and at 1, 2, and 3 h postdrug administration using PANSS (a 30-item rating instrument used to assess psychotic symptoms, with ratings based on a semistructured clinical interview yielding subscores for positive, negative, and general psychopathology domains), the self-administered VAMS with 16 items (e.g., mental sedation or intellectual impairment, physical sedation or bodily impairments, anxiety effects and other types of feelings or attitudes), the ARCI (Addiction Research Center Inventory; containing empirically derived drug-induced euphoria; stimulant-like effects; intellectual efficiency and energy; sedation; dysphoria; and somatic effects) to assess drug effects and the STAI-T/S, where subjects were evaluated on their current mood and their feelings in general.

 

There were no significant differences between the effects of CBD and placebo on positive and negative psychotic symptoms, general psychopathology (PANSS), anxiety (STAI-S), dysphoria (ARCI), sedation (VAMS, ARCI), and the level of subjective intoxication (ASI, ARCI), where Δ9-THC did have a pronounced effect. The physiological parameters, heart rate and blood pressure, were also monitored and no significant difference between the placebo and the CBD group was observed.55

 

Addiction. A case study describes a patient treated for cannabis withdrawal according to the following CBD regimen: “treated with oral 300 mg on Day 1; CBD 600 mg on Days 2–10 (divided into two doses of 300 mg), and CBD 300 mg on Day 11.” CBD treatment resulted in a fast and progressive reduction in withdrawal, dissociative and anxiety symptoms, as measured with the Withdrawal Discomfort Score, the Marijuana Withdrawal Symptom Checklist, Beck Anxiety Inventory, and Beck Depression Inventory (BDI). Hepatic enzymes were also measured daily, but no effect was reported.56

 

Naturalistic studies with smokers inhaling cannabis with varying amounts of CBD showed that the CBD levels were not altering psychomimetic symptoms.1 Interestingly, CBD was able to reduce the “wanting/liking”=implicit attentional bias caused by exposure to cannabis and food-related stimuli. CBD might work to alleviate disorders of addiction, by altering the attentive salience of drug cues. The study did not further measure side effects.57

 

CBD can also reduce heroin-seeking behaviors (e.g., induced by a conditioned cue). This was shown in the preclinical data mentioned earlier and was also replicated in a small double-blind pilot study with individuals addicted to opioids, who have been abstinent for 7 days.52,53 They either received placebo or 400 or 800 mg oral CBD on three consecutive days. Craving was induced with a cue-induced reinstatement paradigm (1 h after CBD administration). One hour after the video session, subjective craving was already reduced after a single CBD administration. The effect persisted for 7 days after the last CBD treatment. Interestingly, anxiety measures were also reduced after treatment, whereas no adverse effects were described.23,58

 

A pilot study with 24 subjects was conducted in a randomized, double-blind, placebo-controlled design to evaluate the impact of the ad hoc use of CBD in smokers, who wished to stop smoking. Pre- and post-testing for mood and craving of the participants was executed. These tests included the Behaviour Impulsivity Scale, BDI, STAI, and the Severity of Dependence Scale. During the week of CBD inhalator use, subjects used a diary to log their craving (on a scale from 1 to 100=VAS measuring momentary subjective craving), the cigarettes smoked, and the number of times they used the inhaler. Craving was assessed using the Tiffany Craving Questionnaire (11). On day 1 and 7, exhaled CO was measured to test smoking status. Sedation, depression, and anxiety were evaluated with the MRS.

 

Over the course of 1 week, participants used the inhaler when they felt the urge to smoke and received a dose of 400 μg CBD via the inhaler (leading to >65% bioavailability); this significantly reduced the number of cigarettes smoked by ca. 40%, while craving was not significantly different in the groups post-test. At day 7, the anxiety levels for placebo and CBD group did not differ. CBD did not increase depression (in contract to the selective CB1 antagonist rimonabant). CBD might weaken the attentional bias to smoking cues or could have disrupted reconsolidation, thereby destabilizing drug-related memories.59

 

Cell Migration

 

According to our literature survey, there currently are no studies about CBD role in embryogenesis/cell migration in humans, even though cell migration does play a role in embryogenesis and CBD was shown to be able to at least influence migratory behavior in cancer.1

 

Endocrine Effects and Glycemic (Including Appetite) Effects

 

To the best of our knowledge, no acute studies were performed that solely concentrated on CBD glycemic effects. Moreover, the only acute study that also measured CBD effect on appetite was the study we described above, comparing different cannabis strains. In this study, the strain high in CBD elicited less appetite increase compared to the THC-only strain.52

 

Eleven healthy volunteers were treated with 300 mg (seven patients) and 600 mg (four patients) oral CBD in a double-blind, placebo-controlled study. Growth hormone and prolactin levels were unchanged. In contrast, the normal decrease of cortisol levels in the morning (basal measurement=11.0±3.7 μg/dl; 120 min after placebo=7.1±3.9 μg/dl) was inhibited by CBD treatment (basal measurement=10.5±4.9 μg/dl; 120 min after 300 mg CBD=9.9±6.2 μg/dl; 120 min after 600 mg CBD=11.6±11.6 μg/dl).60

 

A more recent study also used 600 mg oral CBD for a week and compared 24 healthy subjects to people at risk for psychosis (n=32; 16 received placebo and 16 CBD). Serum cortisol levels were taken before the TSST (Trier Social Stress Test), immediately after, as well as 10 and 20 min after the test. Compared to the healthy individuals, the cortisol levels increased less after TSST in the 32 at-risk individuals. The CBD group showed less reduced cortisol levels but differences were not significant.61 It has to be mentioned that these data were presented at a conference and are not yet published (to our knowledge) in a peer-reviewed journal.

 

Chronic CBD Studies in Humans

 

Truly chronic studies with CBD are still scarce. One can often argue that what the studies call “chronic” CBD administration only differs to acute treatment, because of repeated administration of CBD. Nonetheless, we also included these studies with repeated CBD treatment, because we think that compared to a one-time dose of CBD, repeated CBD regimens add value and knowledge to the field and therefore should be mentioned here.

 

CBD-Drug Interactions

 

An 8-week-long clinical study, including 13 children who were treated for epilepsy with clobazam (initial average dose of 1 mg/kg b.w.) and CBD (oral; starting dose of 5 mg/kg b.w. raised to maximum of 25 mg/kg b.w.), showed the following. The CBD interaction with isozymes CYP3A4 and CYP2C19 caused increased clobazam bioavailability, making it possible to reduce the dose of the antiepileptic drug, which in turn reduced its side effects.62

 

These results are supported by another study described in the review by Grotenhermen et al.63 In this study, 33 children were treated with a daily dose of 5 mg/kg CBD, which was increased every week by 5 mg/kg increments, up to a maximum level of 25 mg/kg. CBD was administered on average with three other drugs, including clobazam (54.5%), valproic acid (36.4%), levetiracetam (30.3%), felbamate (21.2%), lamotrigine (18.2%), and zonisamide (18.2%). The coadministration led to an alteration of blood levels of several antiepileptic drugs. In the case of clobazam this led to sedation, and its levels were subsequently lowered in the course of the study.

 

Physiological Effects

 

A first pilot study in healthy volunteers in 1973 by Mincis et al. administering 10 mg oral CBD for 21 days did not find any neurological and clinical changes (EEG; EKG).64 The same holds true for psychiatry and blood and urine examinations. A similar testing battery was performed in 1980, at weekly intervals for 30 days with daily oral CBD administration of 3 mg/kg b.w., which had the same result.65

 

Neurological and Neuropsychiatric Effects

 

Anxiety. Clinical chronic (lasting longer than a couple of weeks) studies in humans are crucial here but were mostly still lacking at the time of writing this review. They hopefully will shed light on the inconsistencies observerd in animal studies. Chronic studies in humans may, for instance, help to test whether, for example, an anxiolytic effect always prevails after chronic CBD treatment or whether this was an artifact of using different animal models of anxiety or depression.2,18

 

Psychosis and bipolar disorder. In a 4-week open trial, CBD was tested on Parkinson’s patients with psychotic symptoms. Oral doses of 150–400 mg/day CBD (in the last week) were administered. This led to a reduction of their psychotic symptoms. Moreover, no serious side effects or cognitive and motor symptoms were reported.66

 

Bergamaschi et al. describe a chronic study, where a teenager with severe side effects of traditional antipsychotics was treated with up to 1500 mg/day of CBD for 4 weeks. No adverse effects were observed and her symptoms improved. The same positive outcome was registered in another study described by Bergamaschi et al., where three patients were treated with a starting dose of CBD of 40 mg, which was ramped up to 1280 mg/day for 4 weeks.1 A double-blind, randomized clinical trial of CBD versus amisulpride, a potent antipsychotic in acute schizophrenia, was performed on a total of 42 subjects, who were treated for 28 days starting with 200 mg CBD per day each.67 The dose was increased stepwise by 200 mg per day to 4×200 mg CBD daily (total 800 mg per day) within the first week. The respective treatment was maintained for three additional weeks. A reduction of each treatment to 600 mg per day was allowed for clinical reasons, such as unwanted side effects after week 2. This was the case for three patients in the CBD group and five patients in the amisulpride group. While both treatments were effective (no significant difference in PANSS total score), CBD showed the better side effect profile. Amisulpride, working as a dopamine D2/D3-receptor antagonist, is one of the most effective treatment options for schizophrenia. CBD treatment was accompanied by a substantial increase in serum anandamide levels, which was significantly associated with clinical improvement, suggesting inhibition of anandamide deactivation via reduced FAAH activity.

 

In addition, the FAAH substrates palmitoylethanolamide and linoleoyl-ethanolamide (both lipid mediators) were also elevated in the CBD group. CBD showed less serum prolactin increase (predictor of galactorrhoea and sexual dysfunction), fewer extrapyramidal symptoms measured with the Extrapyramidal Symptom Scale, and less weight gain. Moreover, electrocardiograms as well as routine blood parameters were other parameters whose effects were measured but not reported in the study. CBD better safety profile might improve acute compliance and long-term treatment adherence.67,68

 

A press release by GW Pharmaceuticals of September 15th, 2015, described 88 patients with treatment-resistant schizophrenic psychosis, treated either with CBD (in addition to their regular medication) or placebo. Important clinical parameters improved in the CBD group and the number of mild side effects was comparable to the placebo group.2 Table 2 shows an overview of studies with CBD for the treatment of psychotic symptoms and its positive effect on symptomatology and the absence of side effects.69

 

Table 2 Studies with CBD

 

Treatment of two patients for 24 days with 600–1200 mg/day CBD, who were suffering from BD, did not lead to side effects.70 Apart from the study with two patients mentioned above, CBD has not been tested systematically in acute or chronic administration scenarios in humans for BD according to our own literature search.71

 

Epilepsy. Epileptic patients were treated for 135 days with 200–300 mg oral CBD daily and evaluated every week for changes in urine and blood. Moreover, neurological and physiological examinations were performed, which neither showed signs of CBD toxicity nor severe side effects. The study also illustrated that CBD was well tolerated.65

 

A review by Grotenhermen and Müller-Vahl describes several clinical studies with CBD2: 23 patients with therapy-resistant epilepsy (e.g., Dravet syndrome) were treated for 3 months with increasing doses of up to 25 mg/kg b.w. CBD in addition to their regular epilepsy medication. Apart from reducing the seizure frequency in 39% of the patients, the side effects were only mild to moderate and included reduced/increased appetite, weight gain/loss, and tiredness.

 

Another clinical study lasting at least 3 months with 137 children and young adults with various forms of epilepsy, who were treated with the CBD drug Epidiolex, was presented at the American Academy for Neurology in 2015. The patients were suffering from Dravet syndrome (16%), Lennox–Gastaut syndrome (16%), and 10 other forms of epilepsy (some among them were very rare conditions). In this study, almost 50% of the patients experienced a reduction of seizure frequency. The reported side effects were 21% experienced tiredness, 17% diarrhea, and 16% reduced appetite. In a few cases, severe side effects occurred, but it is not clear, if these were caused by Epidiolex. These were status epilepticus (n=10), diarrhea (n=3), weight loss (n=2), and liver damage in one case.

 

The largest CBD study conducted thus far was an open-label study with Epidiolex in 261 patients (mainly children, the average age of the participants was 11) suffering from severe epilepsy, who could not be treated sufficiently with standard medication. After 3 months of treatment, where patients received CBD together with their regular medication, a median reduction of seizure frequency of 45% was observed. Ten percent of the patients reported side effects (tiredness, diarrhea, and exhaustion).2

 

After extensive literature study of the available trials performed until September 2016, CBD side effects were generally mild and infrequent. The only exception seems to be a multicenter open-label study with a total of 162 patients aged 1–30 years, with treatment-resistant epilepsy. Subjects were treated for 1 year with a maximum of 25 mg/kg (in some clinics 50 mg/kg) oral CBD, in addition to their standard medication.

 

This led to a reduction in seizure frequency. In this study, 79% of the cohort experienced side effects. The three most common adverse effects were somnolence (n=41 [25%]), decreased appetite (n=31 [19%]), and diarrhea (n=31 [19%]).72 It has to be pointed out that no control group existed in this study (e.g., placebo or another drug). It is therefore difficult to put the side effect frequency into perspective. Attributing the side effects to CBD is also not straightforward in severely sick patients. Thus, it is not possible to draw reliable conclusions on the causation of the observed side effects in this study.

 

Parkinson’s disease. In a study with a total of 21 Parkinson’s patients (without comorbid psychiatric conditions or dementia) who were treated with either placebo, 75 mg/day CBD or 300 mg/day CBD in an exploratory double-blind trial for 6 weeks, the higher CBD dose showed significant improvement of quality of life, as measured with PDQ-39. This rating instrument comprised the following factors: mobility, activities of daily living, emotional well-being, stigma, social support, cognition, communication, and bodily discomfort. For the factor, “activities of daily living,” a possible dose-dependent relationship could exist between the low and high CBD group—the two CBD groups scored significantly different here. Side effects were evaluated with the UKU (Udvalg for Kliniske Undersøgelser). This assessment instrument analyzes adverse medication effects, including psychic, neurologic, autonomic, and other manifestations. Using the UKU and verbal reports, no significant side effects were recognized in any of the CBD groups.73

 

Huntington’s disease. Fifteen neuroleptic-free patients with Huntington’s disease were treated with either placebo or oral CBD (10 mg/kg b.w. per day) for 6 weeks in a double-blind, randomized, crossover study design. Using various safety outcome variables, clinical tests, and the cannabis side effect inventory, it was shown that there were no differences between the placebo group and the CBD group in the observed side effects.6

 

Immune System

 

Forty-eight patients were treated with 300 mg/kg oral CBD, 7 days before and until 30 days after the transplantation of allogeneic hematopoietic cells from an unrelated donor to treat acute leukemia or myelodysplastic syndrome in combination with standard measures to avoid GVHD (graft vs. host disease; cyclosporine and short course of MTX). The occurrence of various degrees of GVHD was compared with historical data from 108 patients, who had only received the standard treatment. Patients treated with CBD did not develop acute GVHD. In the 16 months after transplantation, the incidence of GHVD was significantly reduced in the CBD group. Side effects were graded using the Common Terminology Criteria for Adverse Events (CTCAE v4.0) classification, which did not detect severe adverse effects.74

 

Endocrine and Glycemic (Including Appetite, Weight Gain) Effects

 

In a placebo-controlled, randomized, double-blind study with 62 subjects with noninsulin-treated type 2 diabetes, 13 patients were treated with twice-daily oral doses of 100 mg CBD for 13 weeks. This resulted in lower resistin levels compared to baseline. The hormone resistin is associated with obesity and insulin resistance. Compared to baseline, glucose-dependent insulinotropic peptide levels were elevated after CBD treatment. This incretin hormone is produced in the proximal duodenum by K cells and has insulinotropic and pancreatic b cell preserving effects. CBD was well tolerated in the patients. However, with the comparatively low CBD concentrations used in this phase-2-trial, no overall improvement of glycemic control was observed.40

 

When weight and appetite were measured as part of a measurement battery for side effects, results were inconclusive. For instance, the study mentioned above, where 23 children with Dravet syndrome were treated, increases as well as decreases in appetite and weight were observed as side effects.2 An open-label trial with 214 patients suffering from treatment-resistant epilepsy showed decreased appetite in 32 cases. However, in the safety analysis group, consisting of 162 subjects, 10 showed decreased weight and 12 had gained weight.52 This could be either due to the fact that CBD only has a small effect on these factors, or appetite and weight are complex endpoints influenced by multiple factors such as diet and genetic predisposition. Both these factors were not controlled for in the reviewed studies.

 

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Dr. Alex Jimenez’s Insight

One of the most crucially important qualities of cannabidiol, or CBD, is its lack of psychoactivity. When taken on its own, consumers can experience the many health benefits of CBD without experiencing the euphoric sensations commonly known to be caused by THC. Cannabidiol acts directly with the endocannabinoid system, an essential system in the human body which many individuals may not be particularly familiar with. When CBD binds to the endocannabinoid system’s receptors, it can stimulate all kinds of changes in the human body. Most of those changes are beneficial, and research studies keep uncovering real and potential medical uses for them.

 

Conclusion

 

This review could substantiate and expand the findings of Bergamaschi et al. about CBD favorable safety profile.1 Nonetheless, various areas of CBD research should be extended. First, more studies researching CBD side effects after real chronic administration need to be conducted. Many so-called chronic administration studies, cited here were only a couple of weeks long. Second, many trials were conducted with a small number of individuals only. To perform a throrough general safety evaluation, more individuals have to be recruited into future clinical trials. Third, several aspects of a toxicological evaluation of a compound such as genotoxicity studies and research evaluating CBD effect on hormones are still scarce. Especially, chronic studies on CBD effect on, for example, genotoxicity and the immune system are still missing. Last, studies that evaluate whether CBD-drug interactions occur in clinical trials have to be performed.

 

In conclusion, CBD safety profile is already established in a plethora of ways. However, some knowledge gaps detailed above should be closed by additional clinical trials to have a completely well-tested pharmaceutical compound.

 

Abbreviations Used

 

  • AD – Alzheimer’s disease
  • ARCI – Addiction Research Center Inventory
  • BD – bipolar disorder
  • BDI – Beck Depression Inventory
  • CBD – cannabidiol
  • HSP – heat shock protein
  • IL – interleukin
  • MRS – Mood Rating Scale
  • PPI – prepulse inhibition
  • ROS – reactive oxygen species
  • SAFTEE – Systematic Assessment for Treatment Emergent Events
  • STAI – State Trait Anxiety Inventory
  • TSST – Trier Social Stress Test
  • UKU – Udvalg for Kliniske Undersøgelser
  • VAMS – Visual Analogue Mood Scale
  • VAS – Visual Analog Scales

 

Acknowledgments

 

The study was commissioned by the European Industrial Hemp Association. The authors thank Michal Carus, Executive Director of the EIHA, for making this review possible, for his encouragement, and helpful hints.

 

Author Disclosure Statement

 

EIHA paid nova-Institute for the review. F.G. is Executive Director of IACM.

 

Chiropractic Care Guide to CBD

 

Chiropractors and health professionals everywhere have become increasingly curious about the health benefits of CBD, or cannabidiol. Below, we will summarize what CBD oil is and we will also discuss its benefits to help guide consumers regarding the use of CBD oil. Incorporating CBD oil into chiropractic care with patients who can benefit from it’s various advantages, may be an innovative approach to help effectively treat a variety of health issues.

 

What is CBD Oil?

 

Cannabidiol, or CBD, is one of the compounds available today with the most growing interest behind its use but it is also one of the most controversial, and consumers worldwide are discovering its own health benefits. CBD is a cannabinoid, a type of over 100 chemical compounds found in the cannabis plant, such as marijuana and hemp. Found in the cannabis plant’s flowers, seeds, and stalks, CBD could be extracted from the plant as part of its cannabis oil. This oil can then be processed into many CBD supplements which can be used to boost well-being and the human body’s ability to keep equilibrium. When CBD oil has been extracted from low-THC hemp, the resulting products are non-psychoactive and safe to use by anyone.

 

How is CBD Used on Patients?

 

These CBD oil products can be given to patients to assist them attain health and wellness by promoting proper sleep, appetite, metabolism, immune reaction, and much more.

 

When CBD petroleum goods are utilized, plant-based cannabinoids or phytocannabinoids such as CBD are consumed by the body in the place where they make their way to the bloodstream and are transported through the body to interact with specific cannabinoid receptors in both peripheral and central nervous systems.

 

The neural communication network that employs these cannabinoid neurotransmitters, known as the endocannabinoid system, plays a fundamental role in the nervous system’s normal functioning. Endocannabinoids, such as anandamide and 2-AG, function as neurotransmitters, delivering chemical messages between nerve cells throughout the nervous system.

 

Phytocannabinoids mimic the functions of the body’s endogenous, or naturally-occurring, cannabinoids like anandamide and 2-AG. CBD and THC’s chemical structures are similar to those of 2-AG and anandamide, letting us use them to control the endocannabinoid system to achieve beneficial effects in the body.

 

CBD oil products come in many different consumption forms, such as capsules, tinctures, topical salves, vaporizers, pure hemp oil oral applicators, and more. These daily use products supply all the benefits of CBD with none of the worry over THC from other medical marijuana solutions.

 

But is CBD Legal?

 

Hemp products, such as nutritional supplements, are lawful in the U.S. provided that they’re manufactured using imported hemp. Hemp is defined at the U.S. as any cannabis plant containing 0.3 percent THC per dry weight or less. At those levels, the THC in hemp-derived CBD petroleum merchandise is far too low to produce psychoactive effects in people. Because our products are derived from low-THC hemp, they’re legal from the U.S. and in over 40 countries globally. However, we suggest you check your regional laws to find out if CBD oil products possess some particular restrictions.

 

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Dr. Alex Jimenez’s Insight

Cannabidiol, or CBD, is a phytocannabinoid which is devoid of psychoactive activity which is why it has been used to provide its many benefits to patients without the side effects commonly associated with THC, or marijuana. Many healthcare professionals, including chiropractors, have started utilizing CBD as a part of their treatment program. Numerous research studies have demonstrated the many health benefits of cannabidiol, or CBD. According to the article above, the favorable safety profile of CBD in humans was confirmed and extended by the reviewed research. Cannabidiol, or CBD, is most often utilized as an adjunct therapy, therefore, it’s interaction with other drugs and/or medications requires further research.

 

Is CBD Safe to Use on Patients?

 

CBD is regarded as safe and nontoxic for humans, even at large quantities. Researchers have conducted numerous studies regarding the use of cannabidiol, or CBD, for its health benefits.

 

In conclusion, the use of cannabidiol, or CBD, has been a controversial topic for many years. However, due to it’s reported health benefits, more and more research studies regarding its advantages in the human body have been conducted in attempts to shine light on the safety and efficiency of this compound as well as thoroughly discussing its side effects. Furthermore, the use of CBD by healthcare professionals, including chiropractors, has become a new treatment approach for a variety of underlying health issues. Further research studies are still required to conclude the health benefits of cannabidiol, or CBD.Information referenced from the National Center for Biotechnology Information (NCBI). The scope of our information is limited to chiropractic as well as to spinal injuries and conditions. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at 915-850-0900 .

 

Curated by Dr. Alex Jimenez

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Additional Topics: Back Pain

Back pain is one of the most prevalent causes for disability and missed days at work worldwide. As a matter of fact, back pain has been attributed as the second most common reason for doctor office visits, outnumbered only by upper-respiratory infections. Approximately 80 percent of the population will experience some type of back pain at least once throughout their life. The spine is a complex structure made up of bones, joints, ligaments and muscles, among other soft tissues. Because of this, injuries and/or aggravated conditions, such as herniated discs, can eventually lead to symptoms of back pain. Sports injuries or automobile accident injuries are often the most frequent cause of back pain, however, sometimes the simplest of movements can have painful results. Fortunately, alternative treatment options, such as chiropractic care, can help ease back pain through the use of spinal adjustments and manual manipulations, ultimately improving pain relief.

 

 

 

blog picture of cartoon paperboy big news

 

EXTRA IMPORTANT TOPIC: Low Back Pain Management

 

MORE TOPICS: EXTRA EXTRA: Chronic Pain & Treatments

 

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Mechanisms of Acute Pain vs Chronic Pain

Mechanisms of Acute Pain vs Chronic Pain

Pain is a very important function of the human body, including the involvement of nociceptors and the central nervous system, or CNS, to transmit messages from noxious stimulation to the brain. Nociceptors are adrenal glands which are responsible for detecting hazardous or harmful stimuli and transmitting electrical signals into the nervous system. The receptors are present in skin, viscera, muscles, joints and meninges to discover a range of stimulation, which might be mechanical, thermal or chemical.

 

There are two types of nociceptors:

 

  • C-fibres would be the most common type and are slow to conduct and respond to stimuli. As the proteins in the membrane of the receptor convert the stimulation into electrical impulses that can be taken through the nervous system.
  • A-delta fibers are known to conduct more rapidly and convey messages of sharp, momentary pain.

 

Additionally, there are silent nociceptors which are usually restricted to stimuli but can be “awoken” with high-intensity mechanical stimulation in response to chemical mediators from the body. Nociceptors may have many different voltage-gated stations for transduction that cause a set of action potentials to commence the electric signaling to the nervous system. The excitability and behavior of the cell are based on the types of channels within the nociceptor.

 

It is important to differentiate between nociception and pain when considering the mechanism of the pain. Nociception is the normal response of the body to noxious stimuli, including reflexes below the suprathreshold that protect the human body from injury. Pain is just perceived when superthreshold for those nociceptors to reach an action possible and initiate the pain pathway is attained, which is comparatively high. The purpose of the article below is to demonstrate the cellular and molecular mechanisms of pain, including acute pain and chronic pain, or persistent pain, as referred to below.

 

Cellular and Molecular Mechanisms of Pain

 

Abstract

 

The nervous system detects and interprets a wide range of thermal and mechanical stimuli as well as environmental and endogenous chemical irritants. When intense, these stimuli generate acute pain, and in the setting of persistent injury, both peripheral and central nervous system components of the pain transmission pathway exhibit tremendous plasticity, enhancing pain signals and producing hypersensitivity. When plasticity facilitates protective reflexes, it can be beneficial, but when the changes persist, a chronic pain condition may result. Genetic, electrophysiological, and pharmacological studies are elucidating the molecular mechanisms that underlie detection, coding, and modulation of noxious stimuli that generate pain.

 

Introduction: Acute Versus Persistent Pain

 

The ability to detect noxious stimuli is essential to an organism’s survival and wellbeing. This is dramatically illustrated by examination of individuals who suffer from congenital abnormalities that render them incapable of detecting painful stimuli. These people cannot feel piercing pain from a sharp object, heat of an open flame, or even discomfort associated with internal injuries, such as a broken bone. As a result, they do not engage appropriate protective behaviors against these conditions, many of which can be life threatening.

 

More commonly, alterations of the pain pathway lead to hypersensitivity, such that pain outlives its usefulness as an acute warning system and instead becomes chronic and debilitating. This may be seen, at some level, as an extension of the normal healing process, whereby tissue or nerve damage elicits hyperactivity to promote guarding of the injured area. For example, sunburn produces temporary sensitization of the affected area. As a result normally innocuous stimuli, such as light touch or warmth, are perceived as painful (a phenomenon referred to as allodynia), or normally painful stimuli elicit pain of greater intensity (referred to as hyperalgesia). At its extreme, the sensitization does not resolve. Indeed, individuals who suffer from arthritis, post-herpetic neuralgia (following a bout of shingles), or bone cancer, experience intense and often unremitting pain that is not only physiologically and psychologically debilitating, but may also hamper recovery. Chronic pain may even persist long after an acute injury, perhaps most commonly experienced as lower back pain or sciatica.

 

Persistent or chronic pain syndromes can be initiated or maintained at peripheral and/or central loci. In either case, the elucidation of molecules and cell types that underlie normal (acute) pain sensation is key to understanding the mechanisms underlying pain hypersensitivity. In the present review we highlight the molecular complexity of the primary afferent nerve fibers that detect noxious stimuli. We not only summarize the processing of acute pain, but also describe how changes in pain processing occur in the setting of tissue or nerve injury.

 

The profound differences between acute and chronic pain emphasize the fact that pain is not generated by an immutable, hard-wired system, but rather results from the engagement of highly plastic molecules and circuits, the molecular biochemical and neuroanatomical basis of which are the focus of current studies. Importantly, this new information has identified a host of potential therapeutic targets for the treatment of pain. We focus here on the peripheral and second order neurons in the spinal cord; the reader is referred to some excellent reviews of supraspinal pain processing mechanisms, which include remarkable insights that imaging studies have brought to the field (Apkarian et al., 2005).

 

Anatomical Overview

 

Nociception is the process by which intense thermal, mechanical or chemical stimuli are detected by a subpopulation of peripheral nerve fibers, called nociceptors (Basbaum and Jessell, 2000). The cell bodies of nociceptors are located in the dorsal root ganglia (DRG) for the body and the trigeminal ganglion for the face, and have both a peripheral and central axonal branch that innervates their target organ and the spinal cord, respectively. Nociceptors are excited only when stimulus intensities reach the noxious range, suggesting that they possess biophysical and molecular properties that enable them to selectively detect and respond to potentially injurious stimuli. There are two major classes of nociceptors. The first includes medium diameter myelinated (Aδ) afferents that mediate acute, well-localized “first” or fast pain. These myelinated afferents differ considerably from the larger diameter and rapidly conducting Aβ fibers that respond to innocuous mechanical stimulation (i.e. light touch). The second class of nociceptor includes small diameter unmyelinated “C” fibers that convey poorly localized, “second” or slow pain.

 

Electrophysiological studies have further subdivided Aδ nociceptors into two main classes. Type I (HTM: high threshold mechanical nociceptors) respond to both mechanical and chemical stimuli, but have relatively high heat thresholds (>50C). If, however, the heat stimulus is maintained, these afferents will respond at lower temperatures. And most importantly, they will sensitize (i.e. the heat or mechanical threshold will drop) in the setting of tissue injury. Type II Aδ nociceptors have a much lower heat threshold, but a very high mechanical threshold. Activity of this afferent almost certainly mediates the “first” acute pain response to noxious heat. Indeed, compression block of myelinated peripheral nerve fibers eliminates first, but not second, pain. By contrast, the Type I fiber likely mediates the first pain provoked by pinprick and other intense mechanical stimuli.

 

The unmyelinated C fibers are also heterogeneous. Like the myelinated afferents, most C fibers are polymodal, that is, they include a population that is both heat and mechanically sensitive (CMHs) (Perl, 2007). Of particular interest are the heat responsive, but mechanically insensitive unmyelinated afferents (so-called silent nociceptors) that develop mechanical sensitivity only in the setting of injury (Schmidt et al., 1995). These afferents are more responsive to chemical stimuli (capsaicin or histamine) compared to the CMHs, and likely come into play when the chemical milieu of inflammation alters their properties. Subsets of these afferents are also responsive to a variety of itch-producing pruritogens. It is worth noting that not all C fibers are nociceptors. Some respond to cooling, and a particularly interesting population of unmyelinated afferents responds to innocuous stroking of the hairy skin, but not to heat or chemical stimulation. These latter fibers appear to mediate pleasant touch (Olausson et al., 2008).

 

Neuroanatomical and molecular characterization of nociceptors has further demonstrated their heterogeneity, particularly for the C fibers (Snider and McMahon, 1998). For example, the so-called ‘peptidergic’ population of C nociceptors releases the neuropeptides, substance P, and calcitonin-gene related peptide (CGRP); they also express the TrkA neurotrophin receptor, which responds to nerve growth factor (NGF). The non-peptidergic population of C nociceptors expresses the c-Ret neurotrophin receptor that is targeted by glial-derived neurotrophic factor (GDNF), as well as neurturin and artemin. A large percentage of the c-Ret-positive population also binds the IB4 isolectin, and expresses G protein-coupled receptors of the Mrg family (Dong et al., 2001), as well as specific purinergic receptor subtypes, notably P2X3. Nociceptors can also be distinguished according to their differential expression of channels that confer sensitivity to heat (TRPV1), cold (TRPM8), acidic milieu (ASICs), and a host of chemical irritants (TRPA1) (Julius and Basbaum, 2001). As noted below, these functionally and molecularly heterogeneous classes of nociceptors associate with specific function in the detection of distinct pain modalities.

 

The Nociceptor: a Bidirectional Signaling Machine

 

One generally thinks of the nociceptor as carrying information in one direction, transmitting noxious stimuli from the periphery to the spinal cord. However, primary afferent fibers have a unique morphology, called pseudo-unipolar, wherein both central and peripheral terminals emanate from a common axonal stalk. The majority of proteins synthesized by the DRG or trigeminal ganglion cell are distributed to both central and peripheral terminals. This distinguishes the primary afferent neuron from the prototypical neuron, where the recipient branch of the neuron (the dendrite) is biochemically distinct from the transmission branch (the axon). The biochemical equivalency of central and peripheral terminals means that the nociceptor can send and receive messages from either end. For example, just as the central terminal is the locus of Ca2+-dependent neurotransmitter release, so the peripheral terminal releases a variety of molecules that influence the local tissue environment. Neurogenic inflammation, in fact, refers to the process whereby peripheral release of the neuropeptides, CGRP and substance P, induces vasodilation and extravasation of plasma proteins, respectively (Basbaum and Jessell, 2000). Furthermore, whereas only the peripheral terminal of the nociceptor will respond to environmental stimuli (painful heat, cold and mechanical stimulation), both the peripheral and central terminals can be targeted by a host of endogenous molecules (such as pH, lipids, and neurotransmitters) that regulate its sensitivity. It follows that therapeutics directed at both terminals can be developed to influence the transmission of pain messages. For example, spinal (intrathecal) delivery of morphine targets opioid receptors expressed by the central terminal of nociceptors, whereas topically applied drugs (such as local anesthetics or capsaicin) regulate pain via an action at the peripheral terminal.

 

Central Projections of the Nociceptor

 

Primary afferent nerve fibers project to the dorsal horn of the spinal cord, which is organized into anatomically and electrophysiological distinct laminae (Basbaum and Jessell, 2000) (Figure 1). For example, Aδ nociceptors project to lamina I as well as to deeper dorsal horn (lamina V). The low threshold, rapidly conducting Aβ afferents, which respond to light touch, project to deep laminae (III, IV, and V). By contrast, C nociceptors project more superficially to laminae I and II.

 

Figure 1 Anatomy of the Pain Pathway

 

This remarkable stratification of afferent subtypes within the superficial dorsal horn is further highlighted by the distinct projection patterns of C nociceptors (Snider and McMahon, 1998). For example, most peptidergic C fibers terminate within lamina I and the most dorsal part of lamina II. By contrast, the nonpeptidergic afferents, including the Mrg-expressing subset, terminate in the mid-region of lamina II. The most ventral part of lamina II is characterized by the presence of excitatory interneurons that express the gamma isoform of protein kinase C (PKC), which has been implicated in injury-induced persistent pain (Malmberg et al., 1997). Recent studies indicate that this PKCγ layer is targeted predominantly by myelinated non-nociceptive afferents (Neumann et al., 2008). Consistent with these anatomical studies, electrophysiological analyses demonstrate that spinal cord neurons within lamina I are generally responsive to noxious stimulation (via Aδ and C fibers), neurons in laminae III and IV are primarily responsive to innocuous stimulation (via Aβ), and neurons in lamina V receive a convergent non-noxious and noxious input via direct (monosynaptic) Aδ and Aβ inputs and indirect (polysynaptic) C fiber inputs. The latter are called wide dynamic range (WDR) neurons, in that they respond to a broad range of stimulus intensities. There is also commonly a visceral input to these WDR neurons, such that the resultant convergence of somatic and visceral likely contributes to the phenomenon of referred pain, whereby pain secondary to an injury affecting a visceral tissue (for example, the heart in angina) is referred to a somatic structure (for example, the shoulder).

 

Ascending Pathways and the Supraspinal Processing of Pain

 

Projection neurons within laminae I and V constitute the major output from the dorsal horn to the brain (Basbaum and Jessell, 2000). These neurons are at the origin of multiple ascending pathways, including the spinothalamic and spinoreticulothalamic tracts, which carry pain messages to the thalamus and brainstem, respectively (Figure 2). The former is particularly relevant to the sensory-discriminative aspects of the pain experience (that is, where is the stimulus and how intense is it?), whereas the latter may be more relevant to poorly localized pains. More recently, attention has focused on spinal cord projections to the parabrachial region of the dorsolateral pons, because the output of this region provides for a very rapid connection with the amygdala, a region generally considered to process information relevant to the aversive properties of the pain experience.

 

Figure 2 Primary Afferent Fibers and Spinal Cord

 

From these brainstem and thalamic loci, information reaches cortical structures. There is no single brain area essential for pain (Apkarian et al., 2005). Rather, pain results from activation of a distributed group of structures, some of which are more associated with the sensory-discriminative properties (such as the somatosensory cortex) and others with the emotional aspects (such as the anterior cingulate gyrus and insular cortex). More recently, imaging studies demonstrate activation of prefrontal cortical areas, as well as regions not generally associated with pain processing (such as the basal ganglia and cerebellum). Whether and to what extent activation of these regions is more related to the response of the individual to the stimulus, or to the perception of the pain is not clear. Finally, Figure 2 illustrates the powerful descending controls that influence (both positive and negatively) the transmission of pain messages at the level of the spinal cord.

 

Acute Pain

 

The primary afferent nerve fiber detects environmental stimuli (of a thermal, mechanical, or chemical nature) and transduces this information into the language of the nervous system, namely electrical current. First, we review progress in understanding the molecular basis of signal detection, and follow this with a brief overview of recent genetic studies that highlight the contribution of voltage-gated channels to pain transmission (Figure 3).

 

Figure 3 Nociceptor Diversity

 

Activating the Nociceptor: Heat

 

Human psychophysical studies have shown that there is a clear and reproducible demarcation between the perception of innocuous warmth and noxious heat, which enables us to recognize and avoid temperatures capable of causing tissue damage. This pain threshold, which typically rests around 43°C, parallels the heat sensitivity of C and Type II Aδ nociceptors described earlier. Indeed, cultured neurons from dissociated dorsal root ganglia show similar heat sensitivity. The majority display a threshold of 43°C, with a smaller cohort activated by more intense heat (threshold >50°C) (Cesare and McNaughton, 1996; Kirschstein et al., 1997; Leffler et al., 2007; Nagy and Rang, 1999). Molecular insights into the process of heat sensation came from the cloning and functional characterization of the receptor for capsaicin, the main pungent ingredient in ‘hot’ chili peppers. Capsaicin and related vanilloid compounds produce burning pain by depolarizing specific subsets of C and Aδ nociceptors through activation of the capsaicin (or vanilloid) receptor, TRPV1, one of approximately 30 members of the greater transient receptor potential (TRP) ion channel family (Caterina et al., 1997). The cloned TRPV1 channel is also gated by increases in ambient temperature, with a thermal activation threshold (∼43°C).

 

Several lines of evidence support the hypothesis that TRPV1 an endogenous transducer of noxious heat. First, TRPV1 is expressed in the majority of heat-sensitive nociceptors (Caterina et al., 1997). Second, capsaicin- and heat-evoked currents are similar, if not identical, in regard to their pharmacological and biophysical properties, as are those of heterologously expressed TRPV1 channels. Third, and as described in greater detail below, TRPV1-evoked responses are markedly enhanced by pro-algesic or pro-inflammatory agents (such as extracellular protons, neurotrophins, or bradykinin), all of which produce hypersensitivity to heat in vivo (Tominaga et al., 1998)). Fourth, analysis of mice lacking this ion channel not only revealed a complete loss of capsaicin sensitivity, but these animals also exhibit significant impairment in their ability to detect and respond to noxious heat (Caterina et al., 2000; Davis et al., 2000). These studies also demonstrated an essential role for this channel in the process whereby tissue injury and inflammation leads to heat hypersensitivity, reflecting the ability of TRPV1 to serve as a molecular integrator of thermal and chemical stimuli (Caterina et al., 2000; Davis et al., 2000).

 

The contribution of TRPV1 to acute heat sensation, however, has been challenged by data collected from an ex vivo preparation in which recordings are obtained from the soma of DRG neurons with intact central and peripheral fibers. In one study, no differences were observed in heat-evoked responses from wild type and TRPV1-deficient animals (Woodbury et al., 2004), but a more recent analysis from this group found that TRPV1-deficient mice do, indeed, lack a cohort of neurons robustly activated by noxious heat (Lawson et al., 2008). Taken together with the results described above we conclude that TRPV1 unquestionably contributes to acute heat sensation, but agree that TRPV1 is not solely responsible for heat transduction.

 

In this regard, whereas TRPV1-deficient mice lack a component of behavioral heat sensitivity, the use of high dose capsaicin to ablate the central terminals of TRPV1-expressing primary afferent fibers results in a more profound, if not complete loss of acute heat pain sensitivity (Cavanaugh et al., 2009). As for the TRPV1 mutant, there is also a loss of tissue injury-evoked heat hyperalgesia. Taken together these results indicate that both the TRPV1-dependent and TRPV1-independent component of noxious heat sensitivity is mediated via TRPV1-expressing nociceptors.

 

What accounts for the TRPV1-independent component of heat sensation? A number of other TRPV channel subtypes, including TRPV2, 3 and 4, have emerged as candidate heat transducers that could potentially cover detection of stimulus intensities flanking that of TRPV1, including both very hot (>50°C) and warm (mid-30°Cs) temperatures (Lumpkin and Caterina, 2007). Heterologously expressed TRPV2 channels display a temperature activation threshold of ∼52°C, whereas TRPV3 and TRPV4 are activated between 25 – 35°C. TRPV2 is expressed in a subpopulation of Aδ neurons that respond to high threshold noxious heat and its biophysical properties resemble those of native high threshold heat-evoked currents (Leffler et al., 2007; Rau et al., 2007). As yet, there are no published reports describing either physiological or behavioral tests of TRPV2 knockout mice. On the other hand, TRPV3- and TRPV4-deficient mice do display altered thermal preference when placed on a surface of graded temperatures, suggesting that these channels contribute in some way to temperature detection in vivo (Guler et al., 2002). Interestingly, both TRPV3 and TRPV4 show substantially greater expression in keratinocytes and epithelial cells compared to sensory neurons, raising the possibility that detection of innocuous heat stimuli involves a functional interplay between skin and the underlying primary afferent fibers (Chung et al., 2003; Peier et al., 2002b).

 

Activating the Nociceptor: Cold

 

As for capsaicin and TRPV1, natural cooling agents, such as menthol and eucalyptol, have been exploited as pharmacological probes to identify and characterize cold-sensitive fibers and cells (Hensel and Zotterman, 1951; Reid and Flonta, 2001) and the molecules that underlie their behavior. Indeed, most cold-sensitive neurons respond to menthol and display a thermal activation threshold of ∼25°C. TRPM8 is a cold and menthol-sen sitive channel whose physiological characteristics match those of native cold currents and TRPM8-deficient mice show a very substantial loss of menthol and cold-evoked responses at the cellular or nerve fiber level. Likewise, these animals display severe deficits in cold-evoked behavioral responses (Bautista et al., 2007; Colburn et al., 2007; Dhaka et al., 2007) over a wide range of temperatures spanning 30 to 10°C. As in the case of TRPV1 and he at, TRPM8-deficient mice are not completely insensitive to cold. For example, there remains a small (∼4%) cohort of cold-sensitive, menthol-insensitive neurons that have a low threshold of activation, of approximately 12°C. These may account for the residual cold sensitivity seen in behavioral tests, wherein TRPM8-deficient animals can still avoid extremely cold surfaces below 10°C. Importantly, TRPM8-deficient mice show normal sensitivity to noxious heat. Indeed, TRPV1 and TRPM8 are expressed in largely non-overlapping neuronal populations, consistent with the notion that hot and cold detection mechanisms are organized into anatomically and functionally distinct ‘labeled lines.’

 

Based on heterologous expression systems, TRPA1 has also been suggested to detect cold, specifically within the noxious (<15°C) range. Moreover TRPA1 is activated by the cooling compounds icilin and menthol (Bandell et al., 2004; Karashima et al., 2007; Story et al., 2003), albeit at relatively high concentrations compared to their actions at TRPM8. However, there continues to be disagreement as to whether native or recombinant TRPA1 are intrinsically cold sensitive (Bandell et al., 2004; Jordt et al., 2004; Karashima et al., 2009; Nagata et al., 2005; Zurborg et al., 2007). This controversy has not been resolved by the analysis of two independent TRPA1-deficient mouse lines. At the cellular level, one study showed normal cold-evoked responses in TRPA1-deficient neurons following a 30 second drop in temperature from 22°C to 4 °C (Bautista et al., 2006); a more recent study has shown a decrease in cold sensitive neurons from 26% (WT) to 10% (TRPA1-/-), when tested after a 200 sec drop in temperature, from 30°C to 10°C (Karashima et al., 2009). In behavioral studies, TRPA1-deficient mice display responses similar to wild-type littermates in the cold-plate and acetone-evoked evaporative cooling assays (Bautista et al., 2006). A second study using the same assays showed that female, but not male, TRPA1 knockout animals displayed attenuated cold sensitivity compared to wild type littermates (Kwan et al., 2006). Karashima et al found no difference in shivering or paw withdrawal latencies in male or female TRPA1-deficient mice on the cold plate test, but observed that prolonged exposure to the cold surface elicited jumping in wild type, but not TRPA1-deficient animals (Karashima et al., 2009). Conceivably, the latter phenotype reflects a contribution of TRPA1 to cold sensitivity in the setting of tissue injury, but not to acute cold pain. Consistent with the latter hypothesis, single nerve fiber recordings show no decrement in acute cold sensitivity in TRPA1-deficient mice (Cavanaugh et al., 2009; Kwan et al., 2009). Finally, it is noteworthy that capsaicin-treated mice lacking the central terminals of TRPV1-expressing fibers show intact behavioral responses to cool and noxious cold stimuli (Cavanaugh et al., 2009). Because TRPA1 is expressed in a subset of TRPV1-positive neurons, it follows that TRPA1 is not required for normal acute cold sensitivity. Future studies using mice deficient for both TRPM8 and TRPA1 will help to resolve these issues and to identify the molecules and cell types that underlie the residual TRPM8-independent component of cold sensitivity.

 

Additional molecules, including voltage-gated sodium channels (discussed below), voltage-gated potassium channels, and two-pore background KCNK potassium channels, coordinate with TRPM8 to fine tune cold thresholds or to propagate cold-evoked action potentials (Viana et al., 2002; Zimmermann et al., 2007; Noel et al., 2009). For example, specific Kv1 inhibitors increase the temperature threshold of cold-sensitive neurons and injection of these inhibitors into the rodent hindpaw reduces behavioral responses to cold, but not to heat or mechanical stimuli (Madrid et al., 2009). Two members of the KCNK channel family, KCNK2 (TREK-1) and KCNK4 (TRAAK) are expressed in a subset of C-fiber nociceptors (Noel et al., 2009) and can be modulated by numerous physiological and pharmacological stimuli, including pressure and temperature. Furthermore, mice lacking these channels display abnormalities in sensitivity to pressure, heat, and cold (Noel et al., 2009). Although these findings suggest that TREK-1 and TRAAK channels modulate nociceptor excitability, it remains unclear how their intrinsic sensitivity to physical stimuli relates to their in vivo contribution to thermal or mechanical transduction.

 

Activating the Nociceptor: Mechanical

 

The somatosensory system detects quantitatively and qualitatively diverse mechanical stimuli, ranging from light brush of the skin to distension of the bladder wall. A variety of mechanosensitive neuronal subtypes are specialized to detect this diverse array of mechanical stimuli and can be categorized according to threshold sensitivity. High threshold mechanoreceptors include C fibers and slowly adapting Aδ mechanoreceptor (AM) fibers, both of which terminate as free nerve endings in the skin. Low threshold mechanoreceptors include Aδ D-hair fibers that terminate on down hairs in the skin and detect light touch. Finally, Aβ fibers that innervate Merkel cells, Pacinian corpuscles and hair follicles detect texture, vibration, and light pressure.

 

As in the case of thermal stimuli, mechanical sensitivity has been probed at a number of levels, including dissociated sensory neurons in culture, ex-vivo fiber recordings, as well as recordings from central (i.e. dorsal horn neurons) and measurements of behavioral output. Ex-vivo skin-nerve recordings have been most informative in matching stimulus properties (such as intensity, frequency, speed, and adaptation) to specific fiber subtypes. For example, Aβ fibers are primarily associated with sensitivity to light touch, whereas C and Aδ fibers are primarily responsive to noxious mechanical insults. At the behavioral level, mechanical sensitivity is typically assessed using two techniques. The most common involves measuring reflex responses to constant force applied to the rodent hind paw by calibrated filaments (Von Frey hairs). The second applies increasing pressure to the paw or tail via a clamp system. In either case, information about mechanical thresholds is obtained under normal (acute) or injury (hypersensitivity) situations. One of the challenges in this area has been to develop additional behavioral assays that measure different aspects of mechanosensation, such as texture discrimination and vibration, which will facilitate the study of both noxious and non-noxious touch (Wetzel et al., 2007).

 

At the cellular level, pressure can be applied to the cell bodies of cultured somatosensory neurons (or to their neurites) using a glass probe, changes in osmotic strength, or stretch via distension of an elastic culture surface, though it is unclear which stimulus best mimics physiological pressure (Bhattacharya et al., 2008; Cho et al., 2006; Cho et al., 2002; Drew et al., 2002; Hu and Lewin, 2006; Lin et al., 2009; Takahashi and Gotoh, 2000). Responses can be assessed using electrophysiological or live cell imaging methods. The consensus from such studies is that that pressure opens a mechanosensitive cation channel to elicit rapid depolarization. However, a dearth of specific pharmacological probes and molecular markers with which to characterize these responses or to label relevant neuronal subtypes has hampered attempts to match cellular activities with anatomically or functionally defined nerve fiber subclasses. These limitations have also impeded the molecular analysis of mechansosensation and the identification of molecules that constitute the mechanotransduction machinery. Nonetheless, a number of candidates have emerged, based largely on studies of mechanosensation in model genetic organisms. Mammalian orthologues of these proteins have been examined using gene targeting approaches in mice, in which the techniques mentioned above can be used to assess deficits in mechanosensation at all levels. Below we briefly summarize some of the candidates revealed in these studies.

 

Candidate Mechanotransducers: DEG/ENaC Channels

 

Studies in the nematode Caenorhabditis elegans (C. elegans) have identified mec-4 and mec-10, members of the degenerin/epithelial Na+ channel (DEG/ENaC) families, as mechanotransducers in body touch neurons (Chalfie, 2009). Based on these studies, the mammalian orthologues ASIC 1, 2 and 3 have been proposed as mechanotransduction channels. ASICs are acid-sensitive ion channels that serve as receptors for extracellular protons (tissue acidosis) produced during ischemia (see below). Although these channels are expressed by both low and high threshold mechanosensitive neurons, genetic studies do not uniformly support an essential role in mechanotransduction. Mice lacking functional ASIC1 channels display normal behavioral responses to cutaneous touch, and little or no change in mechanical sensitivity when assessed by single fiber recording (Page et al., 2004; Price et al., 2000). Likewise, peripheral nerve fibers from ASIC2-deficient mice display only a slight decrease in action potential firing to mechanical stimuli, whereas ASIC3-deficient fibers display a slight increase (no change in mechanical thresholds or baseline behavioral mechanical sensitivity was observed in these animals) (Price et al., 2001; Roza et al., 2004). Analysis of mice deficient for both ASIC2 and ASIC3 also fails to support a role for these channels in cutaneous mechanotransduction (Drew et al., 2004). Thus, although these channels appear to play a role in musculoskeletal and ischemic pain (see below), their contribution to mechanosensation remains unresolved.

 

Genetic studies suggest that C. elegans mec-4/mec-10 channels exist in a complex with the stomatin-like protein MEC-2 (Chalfie, 2009). Mice lacking the MEC-2 orthologue, SLP3, display a loss of mechanosensitivity in low-threshold Aβ and Aδ fibers, but not in C fibers (Wetzel et al., 2007). These mice exhibit altered tactile acuity, but display normal responses to noxious pressure, suggesting that SLP3 contributes to the detection of innocuous, but not noxious mechanical stimuli. Whether SLP3 functions in a mechanotransduction complex or interacts with ASICs in mammalian sensory neurons is unknown.

 

Candidate Mechanotransducers: TRP Channels

 

As noted above, when expressed heterologously, TRPV2 not only responds to noxious heat, but also to osmotic stretch. Additionally, native TRPV2 channels in vascular smooth muscle cells are activated by direct suction and osmotic stimuli (Muraki et al., 2003). A role for TRPV2 for somatosensory mechanotransduction in vivo has not yet been tested.

 

TRPV2 is robustly expressed in medium and large diameter, Aδ fibers that respond to both mechanical and thermal stimuli (Caterina et al., 1999; Muraki et al., 2003). TRPV4 shows modest expression in sensory ganglia, but is more abundantly expressed in the kidney and stretch-sensitive urothelial cells of the bladder (Gevaert et al., 2007; Mochizuki et al., 2009). When heterologously expressed, both TRPV2 and TRPV4 have been shown to respond to changes in osmotic pressure (Guler et al., 2002; Liedtke et al., 2000; Mochizuki et al., 2009; Strotmann et al., 2000). Analysis of TRPV4-deficient animals suggests a role in osmosensation as knockout animals display defects in blood pressure, water balance, and bladder voiding (Gevaert et al., 2007; Liedtke and Friedman, 2003). These animals exhibit normal acute cutaneous mechanosensation, but show deficits in models of mechanical and thermal hyperalgesia (Alessandri-Haber et al., 2006; Chen et al., 2007; Grant et al., 2007; Suzuki et al., 2003). Thus, TRPV4 is unlikely to serve as a primary mechanotransducer in sensory neurons, but may contribute to injury-evoked pain hypersensitivity.

 

TRPA1 has also been proposed to serve as a detector of mechanical stimuli. Heterologously expressed mammalian TRPA1 is activated by membrane crenators (Hill and Schaefer, 2007) and the worm orthologue is sensitive to mechanical pressure applied via a suction pipette (Kindt et al., 2007). However, TRPA1-deficient mice display only weak defects in mechanosensory behavior and the results are inconsistent. Two studies reported no change in mechanical thresholds in TRPA1-deficient animals (Bautista et al., 2006; Petrus et al., 2007), whereas a third study reported deficits (Kwan et al., 2006). A more recent study shows that C and Aβ mechanosensitive fibers in TRPA1 knockout animals have altered responses to mechanical stimulation (some increased and others decreased) (Kwan et al., 2009). Whether and how these differential physiological effects are manifest at the level of behavior is unclear. Taken together, TRPA1 does not appear to function as a primary detector of acute mechanical stimuli, but perhaps modulates excitability of mechanosensitive afferents.

 

Candidate Mechanotransducers: KCNK Channels

 

In addition to the potential mechanotransducer role of KCNK2 and 4 (see above), KCNK18 has been discussed for its possible contribution to mechanosensation. Thus, KCNK18 is targeted by hydroxy-a-sanshool, the pungent ingredient in Szechuan peppercorns that produces tingling and numbing sensations, suggestive of an interaction with touch-sensitive neurons (Bautista et al., 2008; Bryant and Mezine, 1999; Sugai et al., 2005). KCNK18 is expressed in a subset of presumptive peptidergic C fibers and low threshold (Aβ) mechanoreceptors, where it serves as a major regulator of action potential duration and excitability (Bautista et al., 2008; Dobler et al., 2007). Moreover, sanshool depolarizes osmo- and mechanosensitive large diameter sensory neurons, as well as a subset of nociceptors (Bautista et al., 2008; Bhattacharya et al., 2008). Although it is not known if KCNK18 is directly sensitive to mechanical stimulation, it may be a critical regulator of the excitability of neurons involved in innocuous or noxious touch sensation.

 

In summary, the molecular basis of mammalian mechanotransduction is far from clarified. Mechanical hypersensitivity in response to tissue or nerve injury represents a major clinical problem and thus elucidating the biological basis of touch under normal and pathophysiological conditions remains one of the main challenges in somatosensory and pain research.

 

Activating the Nociceptor: Chemical

 

Chemo-nociception is the process by which primary afferent neurons detect environmental irritants and endogenous factors produced by physiological stress. In the context of acute pain, chemo-nociceptive mechanisms trigger aversive responses to a variety of environmental irritants. Here, again, TRP channels have prominent roles, which is perhaps not surprising given that they function as receptors for plant-derived irritants, including capsaicin (TRPV1), menthol (TRPM8), as well as the pungent ingredients in mustard and garlic plants, isothiocyanates and thiosulfinates (TRPA1) (Bandell et al., 2004; Caterina et al., 1997; Jordt et al., 2004; McKemy et al., 2002; Peier et al., 2002a).

 

With respect to environmental irritants, TRPA1 has emerged as a particularly interesting member of this group. This is because TRPA1 responds to compounds that are structurally diverse but unified in their ability to form covalent adducts with thiol groups. For example, allyl isothiocyanate (from wasabi) or allicin (from garlic) are membrane permeable electrophiles that activate TRPA1 by covalently modifying cysteine residues within the amino-terminal cytoplasmic domain of the channel (Hinman et al., 2006; Macpherson et al., 2007). How this promotes channel gating is currently unknown. Nevertheless, simply establishing the importance of thiol reactivity in this process has implicated TRPA1 as a key physiological target for a wide and chemically diverse group of environmental toxicants. One notable example is acrolein (2-propenal), a highly reactive α,β-unsaturated aldehyde present in tear gas, vehicle exhaust, or smoke from burning vegetation (i.e. forest fires and cigarettes). Acrolein and other volatile irritants (such as hypochlorite, hydrogen peroxide, formalin, and isocyanates) activate sensory neurons that innervate the eyes and airways, producing pain and inflammation (Bautista et al., 2006; Bessac and Jordt, 2008; Caceres et al., 2009). This action can have especially dire consequences for those suffering from asthma, chronic cough, or other pulmonary disorders. Mice lacking TRPA1 show greatly reduced sensitivity to such agents, underscoring the critical nature of this channel as a sensory detector of reactive environmental irritants (Caceres et al., 2009). In addition to these environmental toxins, TRPA1 is targeted by some general anesthetics (such as isofluorane) or metabolic byproducts of chemotherapeutic agents (such as cyclophosphamide), which likely underlies some of the adverse side effects of these drugs, including acute pain and robust neuroinflammation (Bautista et al., 2006; Matta et al., 2008).

 

Finally, chemical irritants and other pro-algesic agents are also produced endogenously in response to tissue damage or physiological stress, including oxidative stress. Such factors can act alone, or in combination, to sensitize nociceptors to thermal and/or mechanical stimuli, thereby lowering pain thresholds. The result of this action is to enhance guarding and protective reflexes in the aftermath of injury. Thus, chemo-nociception represents an important interface between acute and persistent pain, especially in the context of peripheral tissue injury and inflammation, as discussed in greater detail below.

 

Acute Pain: Conducting the Pain Signal

 

Once thermal and mechanical signals are transduced by the primary afferent terminal, the receptor potential activates a variety of voltage-gated ion channels. Voltage-gated sodium and potassium channels are critical to the generation of action potentials that convey nociceptor signals to synapses in the dorsal horn. Voltage-gated calcium channels play a key role in neurotransmitter release from central or peripheral nociceptor terminals to generate pain or neurogenic inflammation, respectively. We restrict our discussion to members of the sodium and calcium channel families that serve as targets of currently used analgesic drugs, or for which human genetics support a role in pain transmission. A recent review has discussed the important contribution of KCNQ potassium channels, including the therapeutic benefit of increasing K+ channel activity for the treatment of persistent pain (Brown and Passmore, 2009).

 

Voltage-Gated Sodium Channels

 

A variety of sodium channels are expressed in somatosensory neurons, including the tetrodotoxin (TTX)-sensitive channels Nav1.1, 1.6 and 1.7, and the TTX-insensitive channels, Nav1.8 and 1.9. In recent years, the contribution of Nav1.7 has received much attention, as altered activity of this channel leads to a variety of human pain disorders (Cox et al., 2006; Dib-Hajj et al., 2008). Patients with loss-of-function mutations within this gene are unable to detect noxious stimuli, and as a result suffer injuries due to lack of protective reflexes. In contrast, a number of gain-of-function mutations in Nav1.7 leads to hyperexcitability of the channel and are associated with two distinct pain disorders in humans, erythromelalgia, and paroxysmal extreme pain disorder, both of which cause intense burning sensations (Estacion et al., 2008; Fertleman et al., 2006; Yang et al., 2004). Animal studies have demonstrated that Nav1.7 is highly upregulated in a variety of inflammatory pain models. Indeed, analysis of mice lacking Nav1.7 in C nociceptors supports a key role for this channel in mechanical and thermal hypersensitivity following inflammation, and in acute responses to noxious mechanical stimuli (Nassar et al., 2004). Somewhat surprisingly, pain induced by nerve injury is unaltered, suggesting that distinct sodium channel subtypes, or another population of Nav1.7-expressing afferents, contribute to neuropathic pain (Nassar et al., 2005).

 

The Nav1.8 sodium channel is also highly expressed by most C nociceptors. As with Nav1.7 knockout animals, those lacking Nav1.8 display modest deficits in sensitivity to innocuous or noxious heat, or innocuous pressure; however, they display attenuated responses to noxious mechanical stimuli (Akopian et al., 1999). Nav1.8 is also required for the transmission of cold stimuli, as mice lacking this channel are insensitive to cold over a wide range of temperatures (Zimmermann et al., 2007). This is because Nav1.8 is unique among voltage-sensitive sodium channels in that it does not inactivate at low temperature, making it the predominant action potential generator under cold conditions.

 

Interestingly, transgenic mice lacking the Nav1.8 expressing subset of sensory neurons, which were deleted by targeted expression of diphtheria toxin A (Abrahamsen et al., 2008), display attenuated responses to both low and high threshold mechanical stimuli and cold. In addition, mechanical and thermal hypersensitivity in inflammatory pain models is severely attenuated. The differential phenotypes of mice lacking Nav1.8 channels versus deletion of the Nav1.8-expressing neurons presumably reflects the contribution of multiple voltage-gated sodium channel subtypes to transmission of pain messages.

 

Voltage-gated sodium channels are targets of local anesthetic drugs, highlighting the potential for the development of subtype-specific analgesics. Nav1.7 is a particularly interesting target for treating inflammatory pain syndromes, in part, because the human genetic studies suggest that Nav1.7 inhibitors should reduce pain without altering other essential physiological processes (see above). Another potential application of sodium channel blockers may be to treat extreme hypersensitivity to cold, a particularly troublesome adverse side effect of platinum-based chemotherapeutics, such as oxaliplatin (Attal et al., 2009). Nav1.8 (or TRPM8) antagonists may alleviate this, or other forms of cold allodynia. Finally, the great utility of the antidepressant serotonin and norepinephrine reuptake inhibitors for the treatment of neuropathic pain may, in fact, result from their ability to block voltage gated sodium channels (Dick et al., 2007).

 

Voltage-Gated Calcium Channels

 

A variety of voltage-gated calcium channels are expressed in nociceptors. N-, P/Q- and T-type calcium channels have received the most attention. P/Q-type channels are expressed at synaptic terminals in laminae II-IV of the dorsal horn. Their exact role in nociception is not completely resolved. However, mutations in these channels have been linked to familial hemiplegic migraine (de Vries et al., 2009). N- and T-type calcium channels are also expressed by C-fibers and are upregulated under pathophysiological states, as in models of diabetic neuropathy or after other forms of nerve injury. Animals lacking Cav2.2 or 3.2 show reduced sensitization to mechanical or thermal stimuli following inflammation or nerve injury, respectively (Cao, 2006; Swayne and Bourinet, 2008; Zamponi et al., 2009; Messinger et al., 2009). Moreover, ω-conotoxin GVIA, which blocks N-type channels, is administered intrathecally (as ziconotide) to provide relief for intractable cancer pain (Rauck et al., 2009).

 

All calcium channels are heteromeric proteins composed of α1 pore forming subunits and the modulatory subunits α2δ, α2β or α2γ. The α2δ subunit regulates current density and kinetics of activation and inactivation. In C nociceptors, the α2δ subunit is dramatically upregulated following nerve injury and plays a key role in injury-evoked hypersensitivity and allodynia (Luo et al., 2001). Indeed, this subunit is the target of gabapentinoid class of anticonvulsants, which are now widely used to treat neuropathic pain (Davies et al., 2007).

 

Persistent Pain: Peripheral Mechanisms

 

Persistent pain associated with injury or diseases (such as diabetes, arthritis, or tumor growth) can result from alterations in the properties of peripheral nerves. This can occur as a consequence of damage to nerve fibers, leading to increased spontaneous firing or alterations in their conduction or neurotransmitter properties. In fact, the utility of topical and even systemic local anesthetics for the treatment of different neuropathic pain conditions (such as postherpetic neuralgia) likely reflects their action on sodium channels that accumulate in injured nerve fibers.

 

The Chemical Milieu of Inflammation

 

Peripheral sensitization more commonly results from inflammation-associated changes in the chemical environment of the nerve fiber (McMahon et al., 2008). Thus, tissue damage is often accompanied by the accumulation of endogenous factors released from activated nociceptors or non-neural cells that reside within or infiltrate into the injured area (including mast cells, basophils, platelets, macrophages, neutrophils, endothelial cells, keratinocytes, and fibroblasts). Collectively. these factors, referred to as the ‘inflammatory soup’, represent a wide array of signaling molecules, including neurotransmitters, peptides (substance P, CGRP, bradykinin), eicosinoids and related lipids (prostaglandins, thromboxanes, leukotrienes, endocannabinoids), neurotrophins, cytokines, and chemokines, as well as extracellular proteases and protons. Remarkably, nociceptors express one or more cell surface receptors capable of recognizing and responding to each of these pro-inflammatory or pro-algesic agents (Figure 4). Such interactions enhance excitability of the nerve fiber, thereby heightening its sensitivity to temperature or touch.

 

Figure 4 Peripheral Mediators of Inflammation

 

Unquestionably the most common approach to reducing inflammatory pain involves inhibiting the synthesis or accumulation of components of the inflammatory soup. This is best exemplified by non-steroidal anti-inflammatory drugs, such as aspirin or ibuprofen, which reduce inflammatory pain and hyperalgesia by inhibiting cyclooxygenases (Cox-1 and Cox-2) involved in prostaglandin synthesis. A second approach is to block the actions of inflammatory agents at the nociceptor. Here, we highlight examples that provide new insight into cellular mechanisms of peripheral sensitization, or which form the basis of new therapeutic strategies for treating inflammatory pain.

 

NGF is perhaps best known for its role as a neurotrophic factor required for survival and development of sensory neurons during embryogenesis, but in the adult, NGF is also produced in the setting of tissue injury and constitutes an important component of the inflammatory soup (Ritner et al., 2009). Among its many cellular targets, NGF acts directly on peptidergic C fiber nociceptors, which express the high affinity NGF receptor tyrosine kinase, TrkA, as well as the low affinity neurotrophin receptor, p75 (Chao, 2003; Snider and McMahon, 1998). NGF produces profound hypersensitivity to heat and mechanical stimuli through two temporally distinct mechanisms. At first, a NGF-TrkA interaction activates downstream signaling pathways, including phospholipase C (PLC), mitogen-activated protein kinase (MAPK), and phosphoinositide 3-kinase (PI3K). This results in functional potentiation of target proteins at the peripheral nociceptor terminal, most notably TRPV1, leading to a rapid change in cellular and behavioral heat sensitivity (Chuang et al., 2001). In addition to these rapid actions, NGF is also retrogradely transported to the nucleus of the nociceptor, where it promotes increased expression of pro-nociceptive proteins, including substance P, TRPV1, and the Nav1.8 voltage-gated sodium channel subunit (Chao, 2003; Ji et al., 2002). Together, these changes in gene expression enhance excitability of the nociceptor and amplify the neurogenic inflammatory response.

 

In addition to neurotrophins, injury promotes the release of numerous cytokines, chief among them interleukin 1β (IL-1β) and IL-6, and tumor necrosis factor α (TNF-α) (Ritner et al., 2009). Although there is evidence to support a direct action of these cytokines on nociceptors, their primary contribution to pain hypersensitivity results from potentiation of the inflammatory response and increased production of pro-algesic agents (such as prostaglandins, NGF, bradykinin, and extracellular protons).

 

Irrespective of their pro-nociceptive mechanisms, interfering with neurotrophin or cytokine signaling has become a major strategy for controlling inflammatory disease or resulting pain. The main approach involves blocking NGF or TNF-α action with a neutralizing antibody. In the case of TNF-α, this has been remarkably effective in the treatment of numerous autoimmune diseases, including rheumatoid arthritis, leading to dramatic reduction in both tissue destruction and accompanying hyperalgesia (Atzeni et al., 2005). Because the main actions of NGF on the adult nociceptor occur in the setting of inflammation, the advantage of this approach is that hyperalgesia will decrease without affecting normal pain perception. Indeed, anti-NGF antibodies are currently in clinical trials for treatment of inflammatory pain syndromes (Hefti et al., 2006).

 

Targets of the Inflammatory Soup

 

TRPV1. Robust hypersensitivity to heat can develop with inflammation or after injection of specific components of the inflammatory soup (such as bradykinin or NGF). Lack of such sensitization in TRPV1-deficient mice provides genetic support for the idea that TRPV1 is a key component of the mechanism through which inflammation produces thermal hyperalgesia (Caterina et al., 2000; Davis et al., 2000). Indeed, in vitro studies have shown that TRPV1 functions as a polymodal signal integrator whose thermal sensitivity can be profoundly modulated by components of the inflammatory soup (Tominaga et al., 1998). Some of these inflammatory agents (for example, extracellular protons and lipids) function as direct positive allosteric modulators of the channel, whereas others (bradykinin, ATP, and NGF) bind to their own receptors on primary afferents and modulate TRPV1 through activation of downstream intracellular signaling pathways. In either case, these interactions result in a profound decrease in the channel’s thermal activation threshold, as well as an increase in the magnitude of responses at supra-threshold temperatures—the biophysical equivalents of allodynia and hyperalgesia, respectively.

 

However, there remains controversy concerning the intracellular signaling mechanisms most responsible for TRPV1 modulation (Lumpkin and Caterina, 2007). Reminiscent of ancestral TRP channels in the fly eye, many mammalian TRP channels are activated or positively modulated by phospholipase C-mediated cleavage of plasma membrane phosphatidyl inositol 4,5 bisphosphate (PIP2). Of course, there are many downstream consequences of this action, including a decrease in membrane PIP2, increase levels of diacylglycerol and its metabolites, increased cytoplasmic calcium, as well as consequent activation of protein kinases. In the case of TRPV1, most, if not all, of these pathways have been implicated in the sensitization process and it remains to be seen which are most relevant to behavioral thermal hypersensitivity. Nevertheless, there is broad agreement that TRPV1 modulation is relevant to tissue injury-evoked pain hypersensitivity, particularly in the setting of inflammation. This would include conditions such as sunburn, infection, rheumatoid or osteoarthritis, and inflammatory bowl disease. Another interesting example includes pain from bone cancer (Honore et al., 2009), where tumor growth and bone destruction are accompanied by extremely robust tissue acidosis, as well as production of cytokines, neurotrophins, and prostaglandins.

 

TRPA1. As described above, TRPA1 is activated by compounds that form covalent adducts with cysteine residues. In addition to environmental toxins, this includes endogenous thiol reactive electrophiles that are produced during tissue injury and inflammation, or as a consequence of oxidative or nitrative stress. Chief among such agents are 4-hydroxy-2-nonenal and 15-deoxy-Δ12,14-prostaglandin J2, which are both α,β unsaturated aldehydes generated through peroxidation or spontaneous dehydration of lipid second messengers (Andersson et al., 2008; Cruz-Orengo et al., 2008; Materazzi et al., 2008; Trevisani et al., 2007). Other endogenous TRPA1 agonists include nitrooleic acid, hydrogen peroxide, and hydrogen sulfide. In addition to these directly acting agents, TRPA1 is also modulated indirectly by pro-algesic agents, such as bradykinin, which act via PLC-coupled receptors. Indeed, TRPA1-deficient mice show dramatically reduced cellular and behavioral responses to all of these agents, as well as a reduction in tissue injury-evoked thermal and mechanical hypersensitivity (Bautista et al., 2006; Kwan et al., 2006). Finally, because TRPA1 plays a key role in neurogenic and other inflammatory responses to both endogenous agents and volatile environmental toxins, its contribution to airway inflammation, such as occurs in asthma, is of particular interest. Indeed, genetic or pharmacological blockade of TRPA1 reduces airway inflammation in a rodent model of allergen-evoked asthma (Caceres et al., 2009).

 

ASICs. As noted above, ASIC channels are members of the DEG/ENaC family that are activated by acidification, and thus represent another important site for the action of extracellular protons produced as a consequence of tissue injury or metabolic stress. ASIC subtypes can form a variety of homomeric or heteromeric channels, each having distinct pH sensitivity and expression profile. Channels containing the ASIC3 subtype are specifically expressed by nociceptors and especially well represented in fibers that innervate skeletal and cardiac muscle. In these tissues, anaerobic metabolism leads to buildup of lactic acid and protons, which activate nociceptors to generate musculoskeletal or cardiac pain (Immke and McCleskey, 2001). Interestingly, ASIC3-containing channels open in response to the modest decrease in pH (e.g. 7.4 to 7.0) that occurs with cardiac ischemia (Yagi et al., 2006). Lactic acid also significantly potentiates proton-evoked gating through a mechanism involving calcium chelation (Immke and McCleskey, 2003). Thus, ASIC3-containing channels detect and integrate signals specifically associated with muscle ischemia and, in this way, are functionally distinct from other acid sensors on the primary afferent, such as TRPV1 or other ASIC channel subtypes.

 

Persistent Pain: Central Mechanisms

 

Central sensitization refers to the process through which a state of hyperexcitability is established in the central nervous system, leading to enhanced processing of nociceptive (pain) messages (Woolf, 1983). Although numerous mechanisms have been implicated in central sensitization here we focus on three: alteration in glutamatergic neurotransmission/NMDA receptor-mediated hypersensitivity, loss of tonic inhibitory controls (disinhibition) and glial-neuronal interactions (Figure 5).

 

Figure 5 Spinal Cord Central Sensitization

 

Glutamate/NMDA Receptor-Mediated Sensitization

 

Acute pain is signaled by the release of glutamate from the central terminals of nociceptors, generating excitatory post-synaptic currents (EPSCs) in second order dorsal horn neurons. This occurs primarily through activation of postsynaptic AMPA and kainate subtypes of ionotropic glutamate receptors. Summation of sub-threshold EPSCs in the postsynaptic neuron will eventually result in action potential firing and transmission of the pain message to higher order neurons. Under these conditions, the NMDA subtype of glutamate channel is silent, but in the setting of injury, increased release of neurotransmitters from nociceptors will sufficiently depolarize postsynaptic neurons to activate quiescent NMDA receptors. The consequent increase in calcium influx can strengthen synaptic connections between nociceptors and dorsal horn pain transmission neurons, which in turn will exacerbate responses to noxious stimuli (that is, generate hyperalgesia).

 

In many ways, this processes is comparable to that implicated in the plastic changes associated with hippocampal long-term potentiation (LTP) (for a review on LTP in the pain pathway, see Drdla and Sandkuhler, 2008). Indeed, drugs that block spinal LTP reduce tissue injury-induced hyperalgesia. As in the case of hippocampal LTP, spinal cord central sensitization is dependent on NMDA-mediated elevations of cytosolic Ca2+ in the postsynaptic neuron. Concurrent activation of metabotropic glutamate and substance P receptors on the postsynaptic neuron may also contribute to sensitization by augmenting cytosolic calcium. Downstream activation of a host of signaling pathways and second messenger systems, notably kinases (such as MAPK, PKA, PKC, PI3K, Src), further increases excitability of these neurons, in part by modulating NMDA receptor function (Latremoliere and Woolf, 2009). Illustrative of this model is the demonstration that spinal injections of a nine amino acid peptide fragment of Src not only disrupts an NMDA receptor–Src interaction but also markedly decreases the hypersensitivity produced by peripheral injury, without changing acute pain. Src null mutant mice also display reduced mechanical allodynia after nerve injury (Liu et al., 2008).

 

In addition to enhancing inputs from the site of injury (primary hyperalgesia), central sensitization contributes to the condition in which innocuous stimulation of areas surrounding the injury site can produce pain. This secondary hyperalgesia involves heterosynaptic facilitation, wherein inputs from Aβ afferents, which normally respond to light touch, now engage pain transmission circuits, resulting in profound mechanical allodynia. The fact that compression block of peripheral nerve fibers concurrently interrupts conduction in Aβ afferents and eliminates secondary hyperalgesia indicates that these abnormal circuits are established in clinical settings as well as in animal models (Campbell et al., 1988).

 

Loss of GABAergic and Glycinergic Controls: Disinhibition

 

GABAergic or glycinergic inhibitory interneurons are densely distributed in the superficial dorsal horn and are at the basis of the longstanding gate control theory of pain, which postulates that loss of function of these inhibitory interneurons (disinhibition) would result in increased pain (Melzack and Wall, 1965). Indeed, in rodents, spinal administration of GABA (bicuculline) or glycine (strychnine) receptor antagonists (Malan et al., 2002; Sivilotti and Woolf, 1994; Yaksh, 1989) produces behavioral hypersensitivity resembling that observed after peripheral injury. Consistent with these observations, peripheral injury leads to a decrease in inhibitory postsynaptic currents in superficial dorsal horn neurons. Although Moore et al. (2002) suggested that the disinhibition results from peripheral nerve injury-induced death of GABAergic interneurons, this claim has been contested (Polgar et al., 2005). Regardless of the etiology, the resulting decreased tonic inhibition enhances depolarization and excitation of projection neurons. As for NMDA-mediated central sensitization, disinhibition enhances spinal cord output in response to painful and non-painful stimulation, contributing to mechanical allodynia (Keller et al., 2007; Torsney and MacDermott, 2006).

 

Following upon an earlier report that deletion of the gene encoding PKCγ in the mouse leads to a marked decrease in nerve injury-evoked mechanical hypersensitivity (Malmberg et al., 1997), recent studies address the involvement of these neurons in the disinhibitory process. Thus, after blockade of glycinergic inhibition with strychnine, innocuous brushing of the hindpaw activates PKCγ-positive interneurons in lamina II (Miraucourt et al., 2007), as well as projection neurons in lamina I. Because PKCγ-positive neurons in the spinal cord are located only in the innermost part of lamina II (Figure 1), it follows that these neurons are essential for the expression of nerve injury-evoked persistent pain, and that disinhibitory mechanisms lead to their hyperactivation.

 

Other studies indicate that changes in the projection neuron, itself, contribute to the dis-inhibitory process. For example, peripheral nerve injury profoundly down-regulates the K+-Cl- co-transporter KCC2, which is essential for maintaining normal K+ and Cl- gradients across the plasma membrane (Coull et al., 2003). Downregulating KCC2, which is expressed in lamina I projection neurons, results in a shift in the Cl- gradient, such that activation of GABA-A receptors depolarize, rather than hyperpolarize the lamina I projection neurons. This would, in turn, enhance excitability and increase pain transmission. Indeed, pharmacological blockade or siRNA-mediated downregulation of KCC2 in the rat induces mechanical allodynia. Nonetheless, Zeilhofer and colleagues suggest that, even after injury, sufficient inhibitory tone remains such that enhancement of spinal GABAergic neurotransmission might be a valuable approach to reduce pain hypersensitivity induced by peripheral nerve injury (Knabl et al., 2008). In fact, studies in mice suggest that drugs specifically targeting GABAA complexes containing α2 and/or α3 subunits reduce inflammatory and neuropathic pain without producing sedative-hypnotic side effects typically associated with benzodiazepines, which enhance activity of α1-containing channels.

 

Disinhibition can also occur through modulation of glycinergic signaling. In this case the mechanism involves a spinal cord action of prostaglandins (Harvey et al., 2004). Specifically, tissue injury induces spinal release of the prostaglandin, PGE2, which acts on EP2 receptors expressed by excitatory interneurons and projection neurons in the superficial dorsal horn. Resultant stimulation of the cAMP-PKA pathway phosphorylates GlyRa3 glycine receptor subunits, rendering the neurons unresponsive to the inhibitory effects of glycine. Accordingly, mice lacking the GlyRa3 gene have decreased heat and mechanical hypersensitivity in models of tissue injury.

 

Glial-Neuronal Interactions

 

Finally, glial cells, notably microglia and astrocytes, also contribute to the central sensitization process that occurs in the setting of injury. Under normal conditions, microglia function as resident macrophages of the central nervous system. They are homogeneously distributed within the grey matter of the spinal cord and are presumed to function as sentinels of injury or infection. Within hours of peripheral nerve injury, however, microglia accumulate in the superficial dorsal horn within the termination zone of injured peripheral nerve fibers. Microglia also surround the cell bodies of ventral horn motoneurons, whose peripheral axons are concurrently damaged. The activated microglia release a panoply of signaling molecules, including cytokines (such as TNF-α, interleukin-1β and 6), which enhance neuronal central sensitization and nerve injury-induced persistent pain (DeLeo et al., 2007). Indeed, injection of activated brain microglia into the cerebral spinal fluid at the level of the spinal cord can reproduce the behavioral changes observed after nerve injury (Coull et al., 2005). Thus, it appears that microglial activation is sufficient to trigger the persistent pain condition (Tsuda et al., 2003).

 

As microglia are activated following nerve, but not inflammatory tissue injury, it follows that activation of the afferent fiber, which occurs under both injury conditions, is not the critical trigger for microglial activation. Rather, physical damage of the peripheral afferent must induce the release of specific signals that are detected by microglia. Chief among these is ATP, which targets microglial P2-type purinergic receptors. Of particular interest are P2X4 (Tsuda et al., 2003), P2X7 (Chessell et al., 2005) and P2Y12 (Haynes et al., 2006; Kobayashi et al., 2008) receptor subtypes. Indeed, ATP was used to activate brain microglia in the spinal cord transplant studies referred to above (Tsuda et al., 2003). Furthermore, genetic or pharmacological blockade of purinergic receptor function (Chessell et al., 2005; Tozaki-Saitoh et al., 2008; Ulmann et al., 2008) prevents or reverses nerve injury-induced mechanical allodynia (Honore et al., 2006; Kobayashi et al., 2008; Tozaki-Saitoh et al., 2008; Tsuda et al., 2003).

 

Coull and colleagues proposed a model in which ATP/P2X4-mediated activation of microglia triggers a mechanism of disinhibition (Coull et al., 2005). Specifically, they demonstrated that ATP-evoked activation of P2X4 receptors induces release of the brain-derived neurotrophic factor (BDNF) from microglia. The BDNF, in turn, acts upon TrkB receptors on lamina I projection neurons, to generate a change in the Cl- gradient, which as described above, would shift the action of GABA from hyperpolarization to depolarization. Whether the BDNF-induced effect involves KCC2 expression, as occurs after nerve injury, is not known. Regardless of the mechanism, the net result is that activation of microglia will sensitize lamina I neurons such that their response to monosynaptic inputs from nociceptors, or indirect inputs from Aβ afferents, is enhanced.

 

In addition to BDNF, activated microglia, like peripheral macrophages, release and respond to numerous chemokines and cytokines, and these also contribute to central sensitization. For example, in the uninjured (normal) animal, the chemokine fractalkine (CXCL1) is expressed by both primary afferents and spinal cord neurons (Lindia et al., 2005; Verge et al., 2004; Zhuang et al., 2007). In contrast, the fractalkine receptor (CX3CR1) is expressed on microglial cells and importantly, is upregulated after peripheral nerve injury (Lindia et al., 2005; Zhuang et al., 2007). Because spinal delivery of fractalkine can activate microglia, it appears that nerve injury-induced release of fractalkine provides yet another route through which microglia can be engaged in the process of central sensitization. Indeed blockade of CX3CR1 with a neutralizing antibody prevents both the development and maintenance of injury-induced persistent pain (Milligan et al., 2004; Zhuang et al., 2007). This pathway may also be part of a positive feedback loop through which injured nerve fibers and microglial cells interact in a reciprocal and recurrent fashion to amplify pain signals. This point is underscored by the fact that fractalkine must be cleaved from the neuronal surface prior to signaling, an action that is carried out by the microglial-derived protease, cathepsin S, inhibitors of which reduce nerve injury-induced allodynia and hyperalgesia (Clark et al., 2007). Importantly, spinal administration of cathepsin S generates behavioral hypersensitivity in wild type, but not in CX3CX1 knockout mice, linking cathepsin S to fractalkine signaling (Clark et al., 2007; Zhuang et al., 2007). Although the factor(s) that initiates release of cathepsin S from microglia remains to be determined,. ATP seems a reasonable possibility.

 

Very recently, several members of the Toll-like receptors (TLRs) family have also been implicated in the activation of microglia following nerve injury. TLRs are transmembrane signaling proteins expressed in peripheral immune cells and glia. As part of the innate immune system, they recognize molecules that are broadly shared by pathogens. Genetic or pharmacological inhibition of TLR2, TLR3 or TLR4 function in mice results not only in decreased microglial activation, but also reduces the hypersensitivity triggered by peripheral nerve injury (Kim et al., 2007; Obata et al., 2008; Tanga et al., 2005). Unknown are the endogenous ligands that activate TLR2-4 after nerve-injury. Among the candidates are mRNAs or heat shock proteins that could leak from the damaged primary afferent neurons and diffuse into the extracellular milieu of the spinal cord.

 

The contribution of astrocytes to central sensitization is less clear. Astrocytes are unquestionably induced in the spinal cord after injury to either tissue or nerve (for a review, see Ren and Dubner, 2008). But, in contrast to microglia, astrocyte activation is generally delayed and persists much longer, up to several months. One interesting possibility is that astrocytes are more critical to the maintenance, rather than to the induction of central sensitization and persistent pain.

 

Finally, it is worth noting that peripheral injury not only activates glia in the spinal cord, but also in the brainstem, where glia contribute to supraspinal facilitatory influences on the processing of pain messages in the spinal cord (see Figure 2), a phenomenon named descending facilitation (for a review, see Ren and Dubner, 2008). Such facilitation is especially prominent in the setting of injury, and appears to counteract the feedback inhibitory controls that concurrently arise from various brainstem loci (Porreca et al., 2002).

 

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Dr. Alex Jimenez’s Insight

As established by the International Association for the Study of Pain, or the IASP, pain is “an unpleasant sensory and emotional experience associated with acutal or potential tissue damage, or described in terms of tissue damage or both. Numerous research studies have been proposed to demonstrate the physiological basis of pain, however, none has been able to include the entire aspects associated with pain perception. Understanding the pain mechanisms of acute pain versus chronic pain is fundamental during clinical evaluations as this can help determine the best treatment approach for patients with underlying health issues.

 

Specificity in the Transmission and Control of Pain Messages

 

Understanding how stimuli are encoded by the nervous system to elicit appropriate behaviors is of fundamental importance to the study of all sensory systems. In the simplest form, a sensory system uses labeled lines to transduce stimuli and elicit behaviors through strictly segregated circuits. This is perhaps best exemplified by the taste system, where exchanging a sweet receptor for a bitter one in a population of “sweet taste afferents” does not alter the behavior provoked by activity in that labeled line; under these conditions, a bitter tastant stimulates these afferents to elicit a perception of sweetness (Mueller et al., 2005).

 

In the pain pathway, there is also evidence to support the existence of labeled lines. As mentioned above, heat and cold are detected by largely distinct subsets of primary afferent fibers. Moreover, elimination of subsets of nociceptors can produce selective deficits in the behavioral response to a particular noxious modality. For example, destruction of TRPV1-expressing nociceptors produces a profound loss of heat pain (including heat hyperalgesia), with no change in sensitivity to painful mechanical or cold stimuli. Conversely, deletion of the MrgprD subset of nociceptors results in a highly selective deficit in mechanical responsiveness, with no change in heat sensitivity (Cavanaugh et al., 2009). Further evidence for functional segregation at the level of the nociceptor comes from the analysis of two different opioid receptor subtypes (Scherrer et al., 2009). Specifically, the mu opioid receptor (MOR) predominates in the peptidergic population, whereas the delta opioid receptor (DOR) is expressed in non-peptidergic nociceptors. MOR-selective agonists block heat pain, whereas DOR selective agonists block mechanical pain, again illustrating functional separation of molecularly distinct nociceptor populations.

 

These observations argue for behaviorally-relevant specificity at the level of the nociceptor. However, this is likely to be an oversimplification for at least two reasons. First, many nociceptors are polymodal and can therefore be activated by thermal, mechanical, or chemical stimuli, leaving one to wonder how elimination of large cohorts of nociceptors can have modality-specific effects. This argues for a substantial contribution of spinal circuits to the process whereby nociceptive signals are encoded into distinct pain modalities. Indeed, an important future goal is to better delineate neuronal subtypes within the dorsal horn and characterize their synaptic interactions with functionally or molecularly defined subpopulations of nociceptors. Second, the pain system shows a tremendous capacity for change, particularly in the setting of injury, raising questions about whether and how a labeled line system might accommodate such plasticity, and how alterations in such mechanisms underlie maladaptive changes that produce chronic pain. Indeed, we know that substance P-saporin-mediated deletion of a discrete population of lamina I dorsal horn neurons, which express the substance P receptor, can reduce both the thermal and mechanical pain hypersensitivity that occurs after tissue or nerve injury (Nichols et al., 1999). Such observations suggest that in the setting of injury specificity of the labeled line is not strictly maintained as information is transmitted to higher levels of the neuraxis.

 

Clearly, answers to these questions will require the combined use of anatomical, electrophysiological, and behavioral methods to map the physical and functional circuitry that underlies nociception and pain. The ongoing identification of molecules and genes that mark specific neuronal cell types (both peripheral and central) provides essential tools with which to manipulate genetically or pharmacologically these neurons and to link their activities to specific components of pain behavior under normal and pathophysiological circumstances. Doing so should bring us closer to understanding how acute pain gives way to the maladaptive changes that produce chronic pain, and how this switch can be prevented or reversed.

 

Hemp vs Marijuana - What's the Difference? | El Paso, TX Chiropractor

 

Hemp vs Marijuana: What’s the Difference?

 

With approximately half of U.S. states now permitting the sale of medical marijuana, and a few even allowing the sale of marijuana for recreational use, more and more people are becoming interested in the possible health benefits of this controversial plant.

 

Whilst science on its medical use continues to advance, many people these days are considering how they could access the plant’s health benefits without experiencing its well-known unwanted psychoactive effect. This is completely possible with marijuana’s close relative, hemp but it is essential that you be aware of the difference so that you may be a smart consumer.

 

One Cultivars of the Exact Same Plant

 

Fundamentally, both hemp and marijuana are the exact same plant: Cannabis sativa. There is evidence that Cannabis sativa L has been grown in Asia thousands of years back for its fiber as well as a food supply. Humans eventually realized that the flowering tops of the plant had psychoactive properties. With time, as humans have done so with many other plants, Cannabis farmers began cultivating specific plants to enhance specific properties.

 

Nowadays, though some might argue the true number of plant types, there are really two simple distinctions,

 

Hemp – A plant primarily cultivated outside the United States, although a few U.S. countries let it be grown for study purposes) for use in clothes, paper, biofuels, bioplastics, dietary supplements, cosmetics, and foods. Hemp is cultivated outdoors as a large crop with both male and female plants being present to boost pollination and improve seed production. Legally imported industrial hemp contains less than 0.3 percent of its carcinogenic chemical tetrahydrocannabinol, or THC, content. In reality, legally imported hemp will usually specifically eliminate any extracts in the plant’s dried flowering tops.

 

Marijuana (Marihuana) – Cannabis sativa especially cultivated to enhance its THC content to be used for medicinal or recreational purposes. Marijuana plants are typically grown indoors, under controlled conditions, and growers eliminate all of the male plants from the harvest to prevent fertilization because fertilization lowers the plant’s THC degree.

 

Legality of Medical Marijuana

 

The medical use of marijuana is an increased area of controversy for researchers and consumers alike. Although maybe not quite half of U.S. states have legalized the medical use of this plant, it remains illegal under federal law, and consequently its use remains controversial regardless of the fact that there does seem to be real health benefits for various serious health issues.

 

Those that are looking to use marijuana for medical use should talk about its benefits versus its dangers with a skilled health-care professional before using it. In addition, many consumers who have an interest in its health benefits do not need the psychoactive side effects of THC or the danger of a positive drug test.

 

Hemp: Health Benefits without the Risks

 

Imported hemp, that has a very low, almost absent, level of THC, can be a solution for consumers that are looking for the plant’s health benefits minus the effects of THC.

 

Though THC has some health benefits, hemp comprises more than 80 bioactive compounds that could provide excellent support for a range of health issues, such as stress response, positive mood, and physical discomfort or pain. Hemp can also benefit gastrointestinal health, help keep a healthy inflammatory response throughout the entire body, and support normal immune function.

 

If you are considering the use of a nutritional supplement product which includes hemp, then it’s ideal to buy a product from a trusted source.

 

In conclusion, both the peripheral and central nervous system detect, interpret and regulate a wide range of thermal and mechanical stimulation as well as environmental and endogenous chemical irritants. If the stimuli is too intense, it can generate acute pain where in the instance of persistent or chronic pain, pain transmission can be tremendously affected. The article above describes the cellular and molecular mechanisms of pain for guidance in clinical assessments. Furthermore, the use of hemp can have many health benefits in comparison to the controversial effects of marijuana. Information referenced from the National Center for Biotechnology Information (NCBI). The scope of our information is limited to chiropractic as well as to spinal injuries and conditions. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at 915-850-0900 .

 

Curated by Dr. Alex Jimenez

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Additional Topics: Back Pain

Back pain is one of the most prevalent causes for disability and missed days at work worldwide. As a matter of fact, back pain has been attributed as the second most common reason for doctor office visits, outnumbered only by upper-respiratory infections. Approximately 80 percent of the population will experience some type of back pain at least once throughout their life. The spine is a complex structure made up of bones, joints, ligaments and muscles, among other soft tissues. Because of this, injuries and/or aggravated conditions, such as herniated discs, can eventually lead to symptoms of back pain. Sports injuries or automobile accident injuries are often the most frequent cause of back pain, however, sometimes the simplest of movements can have painful results. Fortunately, alternative treatment options, such as chiropractic care, can help ease back pain through the use of spinal adjustments and manual manipulations, ultimately improving pain relief.

 

 

 

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EXTRA IMPORTANT TOPIC: Low Back Pain Management

 

MORE TOPICS: EXTRA EXTRA: Chronic Pain & Treatments

 

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Brain Changes Associated with Chronic Pain

Brain Changes Associated with Chronic Pain

Pain is the human body’s natural response to injury or illness, and it is often a warning that something is wrong. Once the problem is healed, we generally stop experiencing this painful symptoms, however, what happens when the pain continues long after the cause is gone? Chronic pain is medically defined as persistent pain that lasts 3 to 6 months or more. Chronic pain is certainly a challenging condition to live with, affecting everything from the individual’s activity levels and their ability to work as well as their personal relationships and psychological conditions. But, are you aware that chronic pain may also be affecting the structure and function of your brain? It turns out these brain changes may lead to both cognitive and psychological impairment.

 

Chronic pain doesn’t just influence a singular region of the mind, as a matter of fact, it can result in changes to numerous essential areas of the brain, most of which are involved in many fundamental processes and functions. Various research studies over the years have found alterations to the hippocampus, along with reduction in grey matter from the dorsolateral prefrontal cortex, amygdala, brainstem and right insular cortex, to name a few, associated with chronic pain. A breakdown of a few of the structure of these regions and their related functions might help to put these brain changes into context, for a lot of individuals with chronic pain. The purpose of the following article is to demonstrate as well as discuss the structural and functional brain changes associated with chronic pain, particularly in the case where those reflect probably neither damage nor atrophy.

 

Structural Brain Changes in Chronic Pain Reflect Probably Neither Damage Nor Atrophy

 

Abstract

 

Chronic pain appears to be associated with brain gray matter reduction in areas ascribable to the transmission of pain. The morphological processes underlying these structural changes, probably following functional reorganisation and central plasticity in the brain, remain unclear. The pain in hip osteoarthritis is one of the few chronic pain syndromes which are principally curable. We investigated 20 patients with chronic pain due to unilateral coxarthrosis (mean age 63.25±9.46 (SD) years, 10 female) before hip joint endoprosthetic surgery (pain state) and monitored brain structural changes up to 1 year after surgery: 6–8 weeks, 12–18 weeks and 10–14 month when completely pain free. Patients with chronic pain due to unilateral coxarthrosis had significantly less gray matter compared to controls in the anterior cingulate cortex (ACC), insular cortex and operculum, dorsolateral prefrontal cortex (DLPFC) and orbitofrontal cortex. These regions function as multi-integrative structures during the experience and the anticipation of pain. When the patients were pain free after recovery from endoprosthetic surgery, a gray matter increase in nearly the same areas was found. We also found a progressive increase of brain gray matter in the premotor cortex and the supplementary motor area (SMA). We conclude that gray matter abnormalities in chronic pain are not the cause, but secondary to the disease and are at least in part due to changes in motor function and bodily integration.

 

Introduction

 

Evidence of functional and structural reorganization in chronic pain patients support the idea that chronic pain should not only be conceptualized as an altered functional state, but also as a consequence of functional and structural brain plasticity [1], [2], [3], [4], [5], [6]. In the last six years, more than 20 studies were published demonstrating structural brain changes in 14 chronic pain syndromes. A striking feature of all of these studies is the fact that the gray matter changes were not randomly distributed, but occur in defined and functionally highly specific brain areas – namely, involvement in supraspinal nociceptive processing. The most prominent findings were different for each pain syndrome, but overlapped in the cingulate cortex, the orbitofrontal cortex, the insula and dorsal pons [4]. Further structures comprise the thalamus, dorsolateral prefrontal cortex, basal ganglia and hippocampal area. These findings are often discussed as cellular atrophy, reinforcing the idea of damage or loss of brain gray matter [7], [8], [9]. In fact, researchers found a correlation between brain gray matter decreases and duration of pain [6], [10]. But the duration of pain is also linked to the patient’s age, and the age dependent global, but also regionally specific decline of gray matter is well documented [11]. On the other hand, these structural changes could also be a decrease in cell size, extracellular fluids, synaptogenesis, angiogenesis or even due to blood volume changes [4], [12], [13]. Whatever the source is, for our interpretation of such findings it is important to see these morphometric findings in the light of a wealth of morphometric studies in exercise dependant plasticity, given that regionally specific structural brain changes have been repeatedly shown following cognitive and physical exercise [14].

 

It is not understood why only a relatively small proportion of humans develop a chronic pain syndrome, considering that pain is a universal experience. The question arises whether in some humans a structural difference in central pain transmitting systems may act as a diathesis for chronic pain. Gray matter changes in phantom pain due to amputation [15] and spinal cord injury [3] indicate that the morphological changes of the brain are, at least in part, a consequence of chronic pain. However, the pain in hip osteoarthritis (OA) is one of the few chronic pain syndrome which is principally curable, as 88% of these patients are regularly free of pain following total hip replacement (THR) surgery [16]. In a pilot study we have analysed ten patients with hip OA before and shortly after surgery. We found decreases of gray matter in the anterior cingulated cortex (ACC) and insula during chronic pain before THR surgery and found increases of gray matter in the corresponding brain areas in the pain free condition after surgery [17]. Focussing on this result, we now expanded our studies investigating more patients (n = 20) after successful THR and monitored structural brain changes in four time intervals, up to one year following surgery. To control for gray matter changes due to motor improvement or depression we also administered questionnaires targeting improvement of motor function and mental health.

 

Materials and Methods

 

Volunteers

 

The patients reported here are a subgroup of 20 patients out of 32 patients published recently who were compared to an age- and gender-matched healthy control group [17] but participated in an additional one year follow-up investigation. After surgery 12 patients dropped out because of a second endoprosthetic surgery (n = 2), severe illness (n = 2) and withdrawal of consent (n = 8). This left a group of twenty patients with unilateral primary hip OA (mean age 63.25±9.46 (SD) years, 10 female) who were investigated four times: before surgery (pain state) and again 6–8 and 12–18 weeks and 10–14 months after endoprosthetic surgery, when completely pain free. All patients with primary hip OA had a pain history longer than 12 months, ranging from 1 to 33 years (mean 7.35 years) and a mean pain score of 65.5 (ranging from 40 to 90) on a visual analogue scale (VAS) ranging from 0 (no pain) to 100 (worst imaginable pain). We assessed any occurrence of minor pain events, including tooth-, ear- and headache up to 4 weeks prior to the study. We also randomly selected the data from 20 sex- and age matched healthy controls (mean age 60,95±8,52 (SD) years, 10 female) of the 32 of the above mentioned pilot study [17]. None of the 20 patients or of the 20 sex- and age matched healthy volunteers had any neurological or internal medical history. The study was given ethical approval by the local Ethics committee and written informed consent was obtained from all study participants prior to examination.

 

Behavioural Data

 

We collected data on depression, somatization, anxiety, pain and physical and mental health in all patients and all four time points using the following standardized questionnaires: Beck Depression Inventory (BDI) [18], Brief Symptom Inventory (BSI) [19], Schmerzempfindungs-Skala (SES = pain unpleasantness scale) [20] and Health Survey 36-Item Short Form (SF-36) [21] and the Nottingham Health Profile (NHP). We conducted repeated measures ANOVA and paired two-tailed t-Tests to analyse the longitudinal behavioural data using SPSS 13.0 for Windows (SPSS Inc., Chicago, IL), and used Greenhouse Geisser correction if the assumption for sphericity was violated. The significance level was set at p<0.05.

 

VBM – Data Acquisition

 

Image acquisition. High-resolution MR scanning was performed on a 3T MRI system (Siemens Trio) with a standard 12-channel head coil. For each of the four time points, scan I (between 1 day and 3 month before endoprosthetic surgery), scan II (6 to 8 weeks after surgery), scan III (12 to 18 weeks after surgery) and scan IV (10–14 months after surgery), a T1 weighted structural MRI was acquired for each patient using a 3D-FLASH sequence (TR 15 ms, TE 4.9 ms, flip angle 25°, 1 mm slices, FOV 256×256, voxel size 1×1×1 mm).

 

Image Processing and Statistical Analysis

 

Data pre-processing and analysis were performed with SPM2 (Wellcome Department of Cognitive Neurology, London, UK) running under Matlab (Mathworks, Sherborn, MA, USA) and containing a voxel-based morphometry (VBM)-toolbox for longitudinal data, that is based on high resolution structural 3D MR images and allows for applying voxel-wise statistics to detect regional differences in gray matter density or volumes [22], [23]. In summary, pre-processing involved spatial normalization, gray matter segmentation and 10 mm spatial smoothing with a Gaussian kernel. For the pre-processing steps, we used an optimized protocol [22], [23] and a scanner- and study-specific gray matter template [17]. We used SPM2 rather than SPM5 or SPM8 to make this analysis comparable to our pilot study [17]. as it allows an excellent normalisation and segmentation of longitudinal data. However, as a more recent update of VBM (VBM8) became available recently (http://dbm.neuro.uni-jena.de/vbm/), we also used VBM8.

 

Cross-Sectional Analysis

 

We used a two-sample t-test in order to detect regional differences in brain gray matter between groups (patients at time point scan I (chronic pain) and healthy controls). We applied a threshold of p<0.001 (uncorrected) across the whole brain because of our strong a priory hypothesis, which is based on 9 independent studies and cohorts showing decreases in gray matter in chronic pain patients [7], [8], [9], [15], [24], [25], [26], [27], [28], that gray matter increases will appear in the same (for pain processing relevant) regions as in our pilot study (17). The groups were matched for age and sex with no significant differences between the groups. To investigate whether the differences between groups changed after one year, we also compared patients at time point scan IV (pain free, one year follow-up) to our healthy control group.

 

Longitudinal Analysis

 

To detect differences between time points (Scan I–IV) we compared the scans before surgery (pain state) and again 6–8 and 12–18 weeks and 10–14 months after endoprosthetic surgery (pain free) as repeated measure ANOVA. Because any brain changes due to chronic pain may need some time to recede following operation and cessation of pain and because of the post surgery pain the patients reported, we compared in the longitudinal analysis scan I and II with scan III and IV. For detecting changes that are not closely linked to pain, we also looked for progressive changes over all time intervals. We flipped the brains of patients with OA of the left hip (n = 7) in order to normalize for the side of the pain for both, the group comparison and the longitudinal analysis, but primarily analysed the unflipped data. We used the BDI score as a covariate in the model.

 

Results

 

Behavioral Data

 

All patients reported chronic hip pain before surgery and were pain free (regarding this chronic pain) immediately after surgery, but reported rather acute post-surgery pain on scan II which was different from the pain due to osteoarthritis. The mental health score of the SF-36 (F(1.925/17.322) = 0.352, p = 0.7) and the BSI global score GSI (F(1.706/27.302) = 3.189, p = 0.064) showed no changes over the time course and no mental co-morbidity. None of the controls reported any acute or chronic pain and none showed any symptoms of depression or physical/mental disability.

 

Before surgery, some patients showed mild to moderate depressive symptoms in BDI scores that significantly decreased on scan III (t(17) = 2.317, p = 0.033) and IV (t(16) = 2.132, p = 0.049). Additionally, the SES scores (pain unpleasantness) of all patients improved significantly from scan I (before the surgery) to scan II (t(16) = 4.676, p<0.001), scan III (t(14) = 4.760, p<0.001) and scan IV (t(14) = 4.981, p<0.001, 1 year after surgery) as pain unpleasantness decreased with pain intensity. The pain rating on scan 1 and 2 were positive, the same rating on day 3 and 4 negative. The SES only describes the quality of perceived pain. It was therefore positive on day 1 and 2 (mean 19.6 on day 1 and 13.5 on day 2) and negative (n.a.) on day 3 & 4. However, some patients did not understand this procedure and used the SES as a global “quality of life” measure. This is why all patients were asked on the same day individually and by the same person regarding pain occurrence.

 

In the short form health survey (SF-36), which consists of the summary measures of a Physical Health Score and a Mental Health Score [29], the patients improved significantly in the Physical Health score from scan I to scan II (t(17) = −4.266, p = 0.001), scan III (t(16) = −8.584, p<0.001) and IV (t(12) = −7.148, p<0.001), but not in the Mental Health Score. The results of the NHP were similar, in the subscale “pain” (reversed polarity) we observed a significant change from scan I to scan II (t(14) = −5.674, p<0.001, scan III (t(12) = −7.040, p<0.001 and scan IV (t(10) = −3.258, p = 0.009). We also found a significant increase in the subscale “physical mobility” from scan I to scan III (t(12) = −3.974, p = 0.002) and scan IV (t(10) = −2.511, p = 0.031). There was no significant change between scan I and scan II (six weeks after surgery).

 

Structural Data

 

Cross-sectional analysis. We included age as a covariate in the general linear model and found no age confounds. Compared to sex and age matched controls, patients with primary hip OA (n = 20) showed pre-operatively (Scan I) reduced gray matter in the anterior cingulate cortex (ACC), the insular cortex, operculum, dorsolateral prefrontal cortex (DLPFC), right temporal pole and cerebellum (Table 1 and Figure 1). Except for the right putamen (x = 31, y = −14, z = −1; p<0.001, t = 3.32) no significant increase in gray matter density was found in patients with OA compared to healthy controls. Comparing patients at time point scan IV with matched controls, the same results were found as in the cross-sectional analysis using scan I compared to controls.

 

Figure 1 Statistical Parametric Maps

Figure 1: Statistical parametric maps demonstrating the structural differences in gray matter in patients with chronic pain due to primary hip OA compared to controls and longitudinally compared to themselves over time. Significant gray matter changes are shown superimposed in color, cross-sectional data is depicted in red and longitudinal data in yellow. Axial plane: the left side of the picture is the left side of the brain. top: Areas of significant decrease of gray matter between patients with chronic pain due to primary hip OA and unaffected control subjects. p<0.001 uncorrected bottom: Gray matter increase in 20 pain free patients at the third and fourth scanning period after total hip replacement surgery, as compared to the first (preoperative) and second (6–8 weeks post surgery) scan. p<0.001 uncorrected Plots: Contrast estimates and 90% Confidence interval, effects of interest, arbitrary units. x-axis: contrasts for the 4 timepoints, y-axis: contrast estimate at −3, 50, 2 for ACC and contrast estimate at 36, 39, 3 for insula.

 

Table 1 Cross-Sectional Data

 

Flipping the data of patients with left hip OA (n = 7) and comparing them with healthy controls did not change the results significantly, but for a decrease in the thalamus (x = 10, y = −20, z = 3, p<0.001, t = 3.44) and an increase in the right cerebellum (x = 25, y = −37, z = −50, p<0.001, t = 5.12) that did not reach significance in the unflipped data of the patients compared to controls.

 

Longitudinal analysis. In the longitudinal analysis, a significant increase (p<.001 uncorrected) of gray matter was detected by comparing the first and second scan (chronic pain/post-surgery pain) with the third and fourth scan (pain free) in the ACC, insular cortex, cerebellum and pars orbitalis in the patients with OA (Table 2 and Figure 1). Gray matter decreased over time (p<.001 whole brain analysis uncorrected) in the secondary somatosensory cortex, hippocampus, midcingulate cortex, thalamus and caudate nucleus in patients with OA (Figure 2).

 

Figure 2 Increases in Brain Gray Matter

Figure 2: a) Significant increases in brain gray matter following successful operation. Axial view of significant decrease of gray matter in patients with chronic pain due to primary hip OA compared to control subjects. p<0.001 uncorrected (cross-sectional analysis), b) Longitudinal increase of gray matter over time in yellow comparing scan I&IIscan III>scan IV) in patients with OA. p<0.001 uncorrected (longitudinal analysis). The left side of the picture is the left side of the brain.

 

Table 2 Longitudinal Data

 

Flipping the data of patients with left hip OA (n = 7) did not change the results significantly, but for a decrease of brain gray matter in the Heschl’s Gyrus (x = −41, y = −21, z = 10, p<0.001, t = 3.69) and Precuneus (x = 15, y = −36, z = 3, p<0.001, t = 4.60).

 

By contrasting the first scan (presurgery) with scans 3+4 (postsurgery), we found an increase of gray matter in the frontal cortex and motor cortex (p<0.001 uncorrected). We note that this contrast is less stringent as we have now less scans per condition (pain vs. non-pain). When we lower the threshold we repeat what we have found using contrast of 1+2 vs. 3+4.

 

By looking for areas that increase over all time intervals, we found changes of brain gray matter in motor areas (area 6) in patients with coxarthrosis following total hip replacement (scan I<scan II<scan III<scan IV)). Adding the BDI scores as a covariate did not change the results. Using the recently available software tool VBM8 including DARTEL normalisation (http://dbm.neuro.uni-jena.de/vbm/) we could replicate this finding in the anterior and mid-cingulate cortex and both anterior insulae.

 

We calculated the effect sizes and the cross-sectional analysis (patients vs. controls) yielded a Cohen’s d of 1.78751 in the peak voxel of the ACC (x = −12, y = 25, z = −16). We also calculated Cohen’s d for the longitudinal analysis (contrasting scan 1+2 vs. scan 3+4). This resulted in a Cohen’s d of 1.1158 in the ACC (x = −3, y = 50, z = 2). Regarding the insula (x = −33, y = 21, z = 13) and related to the same contrast, Cohen’s d is 1.0949. Additionally, we calculated the mean of the non-zero voxel values of the Cohen’s d map within the ROI (comprised of the anterior division of the cingulate gyrus and the subcallosal cortex, derived from the Harvard-Oxford Cortical Structural Atlas): 1.251223.

 

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Dr. Alex Jimenez’s Insight

Chronic pain patients can experience a variety of health issues over time, aside from their already debilitating symptoms. For instance, many individuals will experience sleeping problems as a result of their pain, but most importantly, chronic pain can lead to various mental health issues as well, including anxiety and depression. The effects that pain can have on the brain may seem all too overwhelming but growing evidence suggests that these brain changes are not permanent and can be reversed when chronic pain patients receive the proper treatment for their underlying health issues. According to the article, gray matter abnormalities found in chronic pain do not reflect brain damage, but rather, they are a reversible consequence which normalizes when the pain is adequately treated. Fortunately, a variety of treatment approaches are available to help ease chronic pain symptoms and restore the structure and function of the brain.

 

Discussion

 

Monitoring whole brain structure over time, we confirm and expand our pilot data published recently [17]. We found changes in brain gray matter in patients with primary hip osteoarthritis in the chronic pain state, which reverse partly when these patients are pain free, following hip joint endoprosthetic surgery. The partial increase in gray matter after surgery is nearly in the same areas where a decrease of gray matter has been seen before surgery. Flipping the data of patients with left hip OA (and therefore normalizing for the side of the pain) had only little impact on the results but additionally showed a decrease of gray matter in the Heschl’s gyrus and Precuneus that we cannot easily explain and, as no a priori hypothesis exists, regard with great caution. However, the difference seen between patients and healthy controls at scan I was still observable in the cross-sectional analysis at scan IV. The relative increase of gray matter over time is therefore subtle, i.e. not sufficiently distinct to have an effect on the cross sectional analysis, a finding that has already been shown in studies investigating experience dependant plasticity [30], [31]. We note that the fact that we show some parts of brain-changes due to chronic pain to be reversible does not exclude that some other parts of these changes are irreversible.

 

Interestingly, we observed that the gray matter decrease in the ACC in chronic pain patients before surgery seems to continue 6 weeks after surgery (scan II) and only increases towards scan III and IV, possibly due to post-surgery pain, or decrease in motor function. This is in line with the behavioural data of the physical mobility score included in the NHP, which post-operatively did not show any significant change at time point II but significantly increased towards scan III and IV. Of note, our patients reported no pain in the hip after surgery, but experienced post-surgery pain in surrounding muscles and skin which was perceived very differently by patients. However, as patients still reported some pain at scan II, we also contrasted the first scan (pre-surgery) with scans III+IV (post-surgery), revealing an increase of gray matter in the frontal cortex and motor cortex. We note that this contrast is less stringent because of less scans per condition (pain vs. non-pain). When we lowered the threshold we repeat what we have found using contrast of I+II vs. III+IV.

 

Our data strongly suggest that gray matter alterations in chronic pain patients, which are usually found in areas involved in supraspinal nociceptive processing [4] are neither due to neuronal atrophy nor brain damage. The fact that these changes seen in the chronic pain state do not reverse completely could be explained with the relatively short period of observation (one year after operation versus a mean of seven years of chronic pain before the operation). Neuroplastic brain changes that may have developed over several years (as a consequence of constant nociceptive input) need probably more time to reverse completely. Another possibility why the increase of gray matter can only be detected in the longitudinal data but not in the cross-sectional data (i.e. between cohorts at time point IV) is that the number of patients (n = 20) is too small. It needs to be pointed out that the variance between brains of several individuals is quite large and that longitudinal data have the advantage that the variance is relatively small as the same brains are scanned several times. Consequently, subtle changes will only be detectable in longitudinal data [30], [31], [32]. Of course we cannot exclude that these changes are at least partly irreversible although that is unlikely, given the findings of exercise specific structural plasticity and reorganisation [4], [12], [30], [33], [34]. To answer this question, future studies need to investigate patients repeatedly over longer time frames, possibly years.

 

We note that we can only make limited conclusions regarding the dynamics of morphological brain changes over time. The reason is that when we designed this study in 2007 and scanned in 2008 and 2009, it was not known whether structural changes would occur at all and for reasons of feasibility we chose the scan dates and time frames as described here. One could argue that the gray matter changes in time, which we describe for the patient group, might have happened in the control group as well (time effect). However, any changes due to aging, if at all, would be expected to be a decrease in volume. Given our a priori hypothesis, based on 9 independent studies and cohorts showing decreases in gray matter in chronic pain patients [7], [8], [9], [15], [24], [25], [26], [27], [28], we focussed on regional increases over time and therefore believe our finding not to be a simple time effect. Of note, we cannot rule out that the gray matter decrease over time that we found in our patient group could be due to a time effect, as we have not scanned our control group in the same time frame. Given the findings, future studies should aim at more and shorter time intervals, given that exercise dependant morphometric brain changes may occur as fast as after 1 week [32], [33].

 

In addition to the impact of the nociceptive aspect of pain on brain gray matter [17], [34] we observed that changes in motor function probably also contribute to the structural changes. We found motor and premotor areas (area 6) to increase over all time intervals (Figure 3). Intuitively this may be due to improvement of motor function over time as the patients were no more restricted in living a normal life. Notably we did not focus on motor function but an improvement in pain experience, given our original quest to investigate whether the well-known reduction in brain gray matter in chronic pain patients is in principle reversible. Consequently, we did not use specific instruments to investigate motor function. Nevertheless, (functional) motor cortex reorganization in patients with pain syndromes is well documented [35], [36], [37], [38]. Moreover, the motor cortex is one target in therapeutic approaches in medically intractable chronic pain patients using direct brain stimulation [39], [40], transcranial direct current stimulation [41], and repetitive transcranial magnetic stimulation [42], [43]. The exact mechanisms of such modulation (facilitation vs. inhibition, or simply interference in the pain-related networks) are not yet elucidated [40]. A recent study demonstrated that a specific motor experience can alter the structure of the brain [13]. Synaptogenesis, reorganisation of movement representations and angiogenesis in motor cortex may occur with special demands of a motor task. Tsao et al. showed reorganisation in the motor cortex of patients with chronic low back pain that seem to be back pain-specific [44] and Puri et al. observed a reduction in left supplemental motor area gray matter in fibromyalgia sufferers [45]. Our study was not designed to disentangle the different factors that may change the brain in chronic pain but we interpret our data concerning the gray matter changes that they do not exclusively mirror the consequences of constant nociceptive input. In fact, a recent study in neuropathic pain patients pointed out abnormalities in brain regions that encompass emotional, autonomic, and pain perception, implying that they play a critical role in the global clinical picture of chronic pain [28].

 

Figure 3 Statistical Parametric Maps

Figure 3: Statistical parametric maps demonstrating a significant increase of brain gray matter in motor areas (area 6) in patients with coxarthrosis before compared to after THR (longitudinal analysis, scan I<scan II<scan III<scan IV). Contrast estimates at x = 19, y = −12, z = 70.

 

Two recent pilot studies focussed on hip replacement therapy in osteoarthritis patients, the only chronic pain syndrome which is principally curable with total hip replacement [17], [46] and these data are flanked by a very recent study in chronic low back pain patients [47]. These studies need to be seen in the light of several longitudinal studies investigating experience-dependent neuronal plasticity in humans on a structural level [30], [31] and a recent study on structural brain changes in healthy volunteers experiencing repeated painful stimulation [34]. The key message of all these studies is that the main difference in the brain structure between pain patients and controls may recede when the pain is cured. However, it must be taken into account that it is simply not clear whether the changes in chronic pain patients are solely due to nociceptive input or due to the consequences of pain or both. It is more than likely that behavioural changes, such as deprivation or enhancement of social contacts, agility, physical training and life style changes are sufficient to shape the brain [6], [12], [28], [48]. Particularly depression as a co-morbidity or consequence of pain is a key candidate to explain the differences between patients and controls. A small group of our patients with OA showed mild to moderate depressive symptoms that changed with time. We did not find the structural alterations to covary significantly with the BDI-score but the question arises how many other behavioural changes due to the absence of pain and motor improvement may contribute to the results and to what extent they do. These behavioural changes can possibly influence a gray matter decrease in chronic pain as well as a gray matter increase when pain is gone.

 

Another important factor which may bias our interpretation of the results is the fact that nearly all patients with chronic pain took medications against pain, which they stopped when they were pain free. One could argue that NSAIDs such as diclofenac or ibuprofen have some effects on neural systems and the same holds true for opioids, antiepileptics and antidepressants, medications which are frequently used in chronic pain therapy. The impact of pain killers and other medications on morphometric findings may well be important (48). No study so far has shown effects of pain medication on brain morphology but several papers found that changes in brain structure in chronic pain patients are neither solely explained by pain related inactivity [15], nor by pain medication [7], [9], [49]. However, specific studies are lacking. Further research should focus the experience-dependent changes in cortical plasticity, which may have vast clinical implications for the treatment of chronic pain.

 

We also found decreases of gray matter in the longitudinal analysis, possibly due to reorganisation processes that accompany changes in motor function and pain perception. There is little information available about longitudinal changes in brain gray matter in pain conditions, for this reason we have no hypothesis for a gray matter decrease in these areas after the operation. Teutsch et al. [25] found an increase of brain gray matter in the somatosensory and midcingulate cortex in healthy volunteers that experienced painful stimulation in a daily protocol for eight consecutive days. The finding of gray matter increase following experimental nociceptive input overlapped anatomically to some degree with the decrease of brain gray matter in this study in patients that were cured of long-lasting chronic pain. This implies that nociceptive input in healthy volunteers leads to exercise dependant structural changes, as it possibly does in patients with chronic pain, and that these changes reverse in healthy volunteers when nociceptive input stops. Consequently, the decrease of gray matter in these areas seen in patients with OA could be interpreted to follow the same fundamental process: exercise dependant changes brain changes [50]. As a non-invasive procedure, MR Morphometry is the ideal tool for the quest to find the morphological substrates of diseases, deepening our understanding of the relationship between brain structure and function, and even to monitor therapeutic interventions. One of the great challenges in the future is to adapt this powerful tool for multicentre and therapeutic trials of chronic pain.

 

Limitations of this Study

 

Although this study is an extension of our previous study expanding the follow-up data to 12 months and investigating more patients, our principle finding that morphometric brain changes in chronic pain are reversible is rather subtle. The effect sizes are small (see above) and the effects are partly driven by a further reduction of regional brain gray matter volume at the time-point of scan 2. When we exclude the data from scan 2 (directly after the operation) only significant increases in brain gray matter for motor cortex and frontal cortex survive a threshold of p<0.001 uncorrected (Table 3).

 

Table 3 Longitudinal Data

 

Conclusion

 

It is not possible to distinguish to what extent the structural alterations we observed are due to changes in nociceptive input, changes in motor function or medication consumption or changes in well-being as such. Masking the group contrasts of the first and last scan with each other revealed much less differences than expected. Presumably, brain alterations due to chronic pain with all consequences are developing over quite a long time course and may also need some time to revert. Nevertheless, these results reveal processes of reorganisation, strongly suggesting that chronic nociceptive input and motor impairment in these patients leads to altered processing in cortical regions and consequently structural brain changes which are in principle reversible.

 

Acknowledgments

 

We thank all volunteers for the participation in this study and the Physics and Methods group at NeuroImage Nord in Hamburg. The study was given ethical approval by the local Ethics committee and written informed consent was obtained from all study participants prior to examination.

 

Funding Statement

 

This work was supported by grants from the DFG (German Research Foundation) (MA 1862/2-3) and BMBF (The Federal Ministry of Education and Research) (371 57 01 and NeuroImage Nord). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

 

Endocannabinoid System | El Paso, TX Chiropractor

 

The Endocannabinoid System: The Essential System You’ve Never Heard Of

 

In case you haven’t heard of the endocannabinoid system, or ECS, there’s no need to feel embarrassed. Back in the 1960’s, the investigators that became interested in the bioactivity of Cannabis eventually isolated many of its active chemicals. It took another 30 years, however, for researchers studying animal models to find a receptor for these ECS chemicals in the brains of rodents, a discovery which opened a whole world of inquiry into the ECS receptors existence and what their physiological purpose is.

 

We now know that most animals, from fish to birds to mammals, possess an endocannabinoid, and we know that humans not only make their own cannabinoids that interact with this particular system, but we also produce other compounds that interact with the ECS, those of which are observed in many different plants and foods, well beyond the Cannabis species.

 

As a system of the human body, the ECS isn’t an isolated structural platform like the nervous system or cardiovascular system. Instead, the ECS is a set of receptors widely distributed throughout the body which are activated through a set of ligands we collectively know as endocannabinoids, or endogenous cannabinoids. Both verified receptors are just called CB1 and CB2, although there are others which were proposed. PPAR and TRP channels also mediate some functions. Likewise, you will find just two well-documented endocannabinoids: anadamide and 2-arachidonoyl glycerol, or 2-AG.

 

Moreover, fundamental to the endocannabinoid system are the enzymes that synthesize and break down the endocannabinoids. Endocannabinoids are believed to be synthesized in an as-needed foundation. The primary enzymes involved are diacylglycerol lipase and N-acyl-phosphatidylethanolamine-phospholipase D, which respectively synthesize 2-AG and anandamide. The two main degrading enzymes are fatty acid amide hydrolase, or FAAH, which breaks down anandamide, and monoacylglycerol lipase, or MAGL, which breaks down 2-AG. The regulation of these two enzymes may increase or decrease the modulation of the ECS.

 

What is the Function of the ECS?

 

The ECS is the principal homeostatic regulatory system of the body. It may readily be viewed as the body’s internal adaptogenic system, always working to maintain the balance of a variety of function. Endocannabinoids broadly work as neuromodulators and, as such, they regulate a broad range of bodily processes, from fertility to pain. Some of those better-known functions from the ECS are as follows:

 

Nervous System

 

From the central nervous system, or the CNS, general stimulation of the CB1 receptors will inhibit the release of glutamate and GABA. In the CNS, the ECS plays a role in memory formation and learning, promotes neurogenesis in the hippocampus, also regulates neuronal excitability. The ECS also plays a part in the way the brain will react to injury and inflammation. From the spinal cord, the ECS modulates pain signaling and boosts natural analgesia. In the peripheral nervous system, in which CB2 receptors control, the ECS acts primarily in the sympathetic nervous system to regulate functions of the intestinal, urinary, and reproductive tracts.

 

Stress and Mood

 

The ECS has multiple impacts on stress reactions and emotional regulation, such as initiation of this bodily response to acute stress and adaptation over time to more long-term emotions, such as fear and anxiety. A healthy working endocannabinoid system is critical to how humans modulate between a satisfying degree of arousal compared to a level that is excessive and unpleasant. The ECS also plays a role in memory formation and possibly especially in the way in which the brain imprints memories from stress or injury. Because the ECS modulates the release of dopamine, noradrenaline, serotonin, and cortisol, it can also widely influence emotional response and behaviors.

 

Digestive System

 

The digestive tract is populated with both CB1 and CB2 receptors that regulate several important aspects of GI health. It’s thought that the ECS might be the “missing link” in describing the gut-brain-immune link that plays a significant role in the functional health of the digestive tract. The ECS is a regulator of gut immunity, perhaps by limiting the immune system from destroying healthy flora, and also through the modulation of cytokine signaling. The ECS modulates the natural inflammatory response in the digestive tract, which has important implications for a wide range of health issues. Gastric and general GI motility also appears to be partially governed by the ECS.

 

Appetite and Metabolism

 

The ECS, particularly the CB1 receptors, plays a part in appetite, metabolism, and regulation of body fat. Stimulation of the CB1 receptors raises food-seeking behaviour, enhances awareness of smell, also regulates energy balance. Both animals and humans that are overweight have ECS dysregulation that may lead this system to become hyperactive, which contributes to both overeating and reduced energy expenditure. Circulating levels of anandamide and 2-AG have been shown to be elevated in obesity, which might be in part due to decreased production of the FAAH degrading enzyme.

 

Immune Health and Inflammatory Response

 

The cells and organs of the immune system are rich with endocannabinoid receptors. Cannabinoid receptors are expressed in the thymus gland, spleen, tonsils, and bone marrow, as well as on T- and B-lymphocytes, macrophages, mast cells, neutrophils, and natural killer cells. The ECS is regarded as the primary driver of immune system balance and homeostasis. Though not all the functions of the ECS from the immune system are understood, the ECS appears to regulate cytokine production and also to have a role in preventing overactivity in the immune system. Inflammation is a natural part of the immune response, and it plays a very normal role in acute insults to the body, including injury and disease ; nonetheless, when it isn’t kept in check it can become chronic and contribute to a cascade of adverse health problems, such as chronic pain. By keeping the immune response in check, the ECS helps to maintain a more balanced inflammatory response through the body.

 

Other areas of health regulated by the ECS:

 

  • Bone health
  • Fertility
  • Skin health
  • Arterial and respiratory health
  • Sleep and circadian rhythm

 

How to best support a healthy ECS is a question many researchers are now trying to answer. Stay tuned for more information on this emerging topic.

 

In conclusion, chronic pain has been associated with brain changes, including the reduction of gray matter. However, the article above demonstrated that chronic pain can alter the overall structure and function of the brain. Although chronic pain may lead to these, among other health issues, the proper treatment of the patient’s underlying symptoms can reverse brain changes and regulate gray matter. Furthermore, more and more research studies have emerged behind the importance of the endocannabinoid system and it’s function in controlling as well as managing chronic pain and other health issues. Information referenced from the National Center for Biotechnology Information (NCBI). The scope of our information is limited to chiropractic as well as to spinal injuries and conditions. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at 915-850-0900 .

 

Curated by Dr. Alex Jimenez

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Additional Topics: Back Pain

Back pain is one of the most prevalent causes for disability and missed days at work worldwide. As a matter of fact, back pain has been attributed as the second most common reason for doctor office visits, outnumbered only by upper-respiratory infections. Approximately 80 percent of the population will experience some type of back pain at least once throughout their life. The spine is a complex structure made up of bones, joints, ligaments and muscles, among other soft tissues. Because of this, injuries and/or aggravated conditions, such as herniated discs, can eventually lead to symptoms of back pain. Sports injuries or automobile accident injuries are often the most frequent cause of back pain, however, sometimes the simplest of movements can have painful results. Fortunately, alternative treatment options, such as chiropractic care, can help ease back pain through the use of spinal adjustments and manual manipulations, ultimately improving pain relief.

 

 

 

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EXTRA IMPORTANT TOPIC: Low Back Pain Management

 

MORE TOPICS: EXTRA EXTRA: Chronic Pain & Treatments

 

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8. Rocca MA, Ceccarelli A, Falini A, Colombo B, Tortorella P, et al. (2006) Brain gray matter changes in migraine patients with T2-visible lesions: a 3-T MRI studyStroke 37: 1765–1770. [PubMed]
9. Kuchinad A, Schweinhardt P, Seminowicz DA, Wood PB, Chizh BA, et al. (2007) Accelerated brain gray matter loss in fibromyalgia patients: premature aging of the brain? J Neurosci 27: 4004–4007.[PubMed]
10. Tracey I, Bushnell MC (2009) How neuroimaging studies have challenged us to rethink: is chronic pain a disease? J Pain 10: 1113–1120. [PubMed]
11. Franke K, Ziegler G, Kloppel S, Gaser C (2010) Estimating the age of healthy subjects from T1-weighted MRI scans using kernel methods: exploring the influence of various parametersNeuroimage 50: 883–892. [PubMed]
12. Draganski B, May A (2008) Training-induced structural changes in the adult human brainBehav Brain Res 192: 137–142. [PubMed]
13. Adkins DL, Boychuk J, Remple MS, Kleim JA (2006) Motor training induces experience-specific patterns of plasticity across motor cortex and spinal cordJ Appl Physiol 101: 1776–1782. [PubMed]
14. Duerden EG, Laverdure-Dupont D (2008) Practice makes cortexJ Neurosci 28: 8655–8657. [PubMed]
15. Draganski B, Moser T, Lummel N, Ganssbauer S, Bogdahn U, et al. (2006) Decrease of thalamic gray matter following limb amputationNeuroimage 31: 951–957. [PubMed]
16. Nikolajsen L, Brandsborg B, Lucht U, Jensen TS, Kehlet H (2006) Chronic pain following total hip arthroplasty: a nationwide questionnaire studyActa Anaesthesiol Scand 50: 495–500. [PubMed]
17. Rodriguez-Raecke R, Niemeier A, Ihle K, Ruether W, May A (2009) Brain gray matter decrease in chronic pain is the consequence and not the cause of painJ Neurosci 29: 13746–13750. [PubMed]
18. Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J (1961) An inventory for measuring depressionArch Gen Psychiatry 4: 561–571. [PubMed]
19. Franke G (2002) Die Symptom-Checkliste nach L.R. Derogatis – Manual. Göttingen Beltz Test Verlag.
20. Geissner E (1995) The Pain Perception Scale–a differentiated and change-sensitive scale for assessing chronic and acute pain. Rehabilitation (Stuttg) 34: XXXV–XLIII. [PubMed]
21. Bullinger M, Kirchberger I (1998) SF-36 – Fragebogen zum Gesundheitszustand. Hand-anweisung. Göttingen: Hogrefe.
22. Ashburner J, Friston KJ (2000) Voxel-based morphometry–the methodsNeuroimage 11: 805–821.[PubMed]
23. Good CD, Johnsrude IS, Ashburner J, Henson RN, Friston KJ, et al. (2001) A voxel-based morphometric study of ageing in 465 normal adult human brainsNeuroimage 14: 21–36. [PubMed]
24. Baliki MN, Chialvo DR, Geha PY, Levy RM, Harden RN, et al. (2006) Chronic pain and the emotional brain: specific brain activity associated with spontaneous fluctuations of intensity of chronic back painJ Neurosci 26: 12165–12173. [PMC free article] [PubMed]
25. Lutz J, Jager L, de Quervain D, Krauseneck T, Padberg F, et al. (2008) White and gray matter abnormalities in the brain of patients with fibromyalgia: a diffusion-tensor and volumetric imaging studyArthritis Rheum 58: 3960–3969. [PubMed]
26. Wrigley PJ, Gustin SM, Macey PM, Nash PG, Gandevia SC, et al. (2008) Anatomical Changes in Human Motor Cortex and Motor Pathways following Complete Thoracic Spinal Cord InjuryCereb Cortex19: 224–232. [PubMed]
27. Schmidt-Wilcke T, Hierlmeier S, Leinisch E (2010) Altered Regional Brain Morphology in Patients With Chronic Facial Pain. Headache. [PubMed]
28. Geha PY, Baliki MN, Harden RN, Bauer WR, Parrish TB, et al. (2008) The brain in chronic CRPS pain: abnormal gray-white matter interactions in emotional and autonomic regionsNeuron 60: 570–581. [PMC free article] [PubMed]
29. Brazier J, Roberts J, Deverill M (2002) The estimation of a preference-based measure of health from the SF-36J Health Econ 21: 271–292. [PubMed]
30. Draganski B, Gaser C, Busch V, Schuierer G, Bogdahn U, et al. (2004) Neuroplasticity: changes in grey matter induced by trainingNature 427: 311–312. [PubMed]
31. Boyke J, Driemeyer J, Gaser C, Buchel C, May A (2008) Training-induced brain structure changes in the elderlyJ Neurosci 28: 7031–7035. [PubMed]
32. Driemeyer J, Boyke J, Gaser C, Buchel C, May A (2008) Changes in gray matter induced by learning–revisitedPLoS ONE 3: e2669. [PMC free article] [PubMed]
33. May A, Hajak G, Ganssbauer S, Steffens T, Langguth B, et al. (2007) Structural brain alterations following 5 days of intervention: dynamic aspects of neuroplasticityCereb Cortex 17: 205–210. [PubMed]
34. Teutsch S, Herken W, Bingel U, Schoell E, May A (2008) Changes in brain gray matter due to repetitive painful stimulationNeuroimage 42: 845–849. [PubMed]
35. Flor H, Braun C, Elbert T, Birbaumer N (1997) Extensive reorganization of primary somatosensory cortex in chronic back pain patientsNeurosci Lett 224: 5–8. [PubMed]
36. Flor H, Denke C, Schaefer M, Grusser S (2001) Effect of sensory discrimination training on cortical reorganisation and phantom limb painLancet 357: 1763–1764. [PubMed]
37. Swart CM, Stins JF, Beek PJ (2009) Cortical changes in complex regional pain syndrome (CRPS)Eur J Pain 13: 902–907. [PubMed]
38. Maihofner C, Baron R, DeCol R, Binder A, Birklein F, et al. (2007) The motor system shows adaptive changes in complex regional pain syndromeBrain 130: 2671–2687. [PubMed]
39. Fontaine D, Hamani C, Lozano A (2009) Efficacy and safety of motor cortex stimulation for chronic neuropathic pain: critical review of the literatureJ Neurosurg 110: 251–256. [PubMed]
40. Levy R, Deer TR, Henderson J (2010) Intracranial neurostimulation for pain control: a reviewPain Physician 13: 157–165. [PubMed]
41. Antal A, Brepohl N, Poreisz C, Boros K, Csifcsak G, et al. (2008) Transcranial direct current stimulation over somatosensory cortex decreases experimentally induced acute pain perceptionClin J Pain24: 56–63. [PubMed]
42. Teepker M, Hotzel J, Timmesfeld N, Reis J, Mylius V, et al. (2010) Low-frequency rTMS of the vertex in the prophylactic treatment of migraineCephalalgia 30: 137–144. [PubMed]
43. O’Connell N, Wand B, Marston L, Spencer S, Desouza L (2010) Non-invasive brain stimulation techniques for chronic pain. A report of a Cochrane systematic review and meta-analysisEur J Phys Rehabil Med 47: 309–326. [PubMed]
44. Tsao H, Galea MP, Hodges PW (2008) Reorganization of the motor cortex is associated with postural control deficits in recurrent low back painBrain 131: 2161–2171. [PubMed]
45. Puri BK, Agour M, Gunatilake KD, Fernando KA, Gurusinghe AI, et al. (2010) Reduction in left supplementary motor area grey matter in adult female fibromyalgia sufferers with marked fatigue and without affective disorder: a pilot controlled 3-T magnetic resonance imaging voxel-based morphometry studyJ Int Med Res 38: 1468–1472. [PubMed]
46. Gwilym SE, Fillipini N, Douaud G, Carr AJ, Tracey I (2010) Thalamic atrophy associated with painful osteoarthritis of the hip is reversible after arthroplasty; a longitudinal voxel-based-morphometric study. Arthritis Rheum. [PubMed]
47. Seminowicz DA, Wideman TH, Naso L, Hatami-Khoroushahi Z, Fallatah S, et al. (2011) Effective treatment of chronic low back pain in humans reverses abnormal brain anatomy and functionJ Neurosci31: 7540–7550. [PubMed]
48. May A, Gaser C (2006) Magnetic resonance-based morphometry: a window into structural plasticity of the brainCurr Opin Neurol 19: 407–411. [PubMed]
49. Schmidt-Wilcke T, Leinisch E, Straube A, Kampfe N, Draganski B, et al. (2005) Gray matter decrease in patients with chronic tension type headacheNeurology 65: 1483–1486. [PubMed]
50. May A (2009) Morphing voxels: the hype around structural imaging of headache patientsBrain 132(Pt6): 1419–1425. [PubMed]
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The Connection Between Anxiety and Inflammation

The Connection Between Anxiety and Inflammation

Anxiety is the most common mental health disorder in the United States, impacting more than 40 million adults. Though some instances can be moderate and short-lived, others may be painfully debilitating, lasting for years, or becoming a chronic problem. While almost anyone can experience temporary anxiety before a variety of events, anxiety is regarded as problematic when it starts to interfere in one way or another with regular, everyday function, including sleep disturbances, social stress, or self-care. Anxiety is connected to a number of lifestyle, health, and nutritional aspects, but understanding the triggers and root causes can result in a more effective treatment approach.

 

The thought of the existence of an interaction between the immune system and the central nervous system, or CNS, has prompted extensive research attention into the subject of “psychoneuroimmunology”, carrying the area to an intriguing level where new hypotheses are being increasingly tested. So far, the presence of inflammatory reactions and the crucial effects of depression have received most attention. But considering a large socioeconomic impact due to an alarming increase in anxiety disorder patients, there is an urgent research need for better comprehension of the role of inflammation in anxiety and how this relationship can influence one another. The purpose of the article below is to demonstrate the results as well as discuss the outcome measures of a large cohort study conducted in order to determine the possible connection between anxiety disorders and brain inflammation.

 

Anxiety Disorders and Inflammation in a Large Adult Cohort

 

Abstract

 

Although anxiety disorders, like depression, are increasingly being associated with metabolic and cardiovascular burden, in contrast with depression, the role of inflammation in anxiety has sparsely been examined. This large cohort study examines the association between anxiety disorders and anxiety characteristics with several inflammatory markers. For this purpose, persons (18–65 years) with a current (N=1273) or remitted (N=459) anxiety disorder (generalized anxiety disorder, social phobia, panic disorder, agoraphobia) according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria and healthy controls (N=556) were selected from the Netherlands Study of Depression and Anxiety. In addition, severity, duration, age of onset, anxiety subtype and co-morbid depression were assessed. Inflammatory markers included C-reactive protein (CRP), interleukin (IL)-6 and tumor-necrosis factor (TNF)-α. Results show that after adjustment for sociodemographics, lifestyle and disease, elevated levels of CRP were found in men, but not in women, with a current anxiety disorder compared with controls (1.18 (s.e.=1.05) versus 0.98 (s.e.=1.07) mg l−1, P=0.04, Cohen’s d=0.18). No associations were found with IL-6 or TNF-α. Among persons with a current anxiety disorder, those with social phobia, in particular women, had lower levels of CRP and IL-6, whereas highest CRP levels were found in those with an older age of anxiety disorder onset. Especially in persons with an age of onset after 50 years, CRP levels were increased compared with controls (1.95 (s.e.=1.18) versus 1.27 (s.e.=1.05) mg l−1, P=0.01, Cohen’s d=0.37). In conclusion, elevated inflammation is present in men with current anxiety disorders. Immune dysregulation is especially found in persons with a late-onset anxiety disorder, suggesting the existence of a specific late-onset anxiety subtype with a distinct etiology, which could possibly benefit from alternative treatments.

 

Keywords: anxiety disorder, anxiety characteristics, cohort study, inflammation

 

Introduction

 

Anxiety disorders are among the most prevalent and disabling mental disorders.1, 2 Increasing evidence links anxiety to cardiovascular risk factors and diseases such as atherosclerosis,3 metabolic syndrome,4 and coronary heart disease.5, 6 As low-grade systemic inflammation is clearly involved in the etiology of these somatic conditions,7, 8, 9 it has been hypothesized that inflammation has a role in anxiety disorders and may form the link between anxiety disorders and cardiovascular burden.10 Anxiety disorders are also highly co-morbid with depression,11 which has recurrently been associated with immune dysregulation.12, 13 However, unlike depression, very few studies have investigated the relationship between anxiety disorders and inflammation. Two recent studies have correlated anxiety symptoms with increased cytokine levels, in particular C-reactive protein (CRP).14, 15 With regard to anxiety disorders, research has mainly focused on posttraumatic stress disorder, in which high levels of inflammatory markers have been found.16, 17 Sparse evidence from relatively small clinical studies (n≈100) suggests increased inflammatory activation in patients with panic disorder18 and generalized anxiety disorder,19 which seems to be independent of co-morbid depression.

 

As there is yet limited research on immune dysregulation and anxiety, one can only speculate on the mechanisms linking these two conditions. Experimentally induced stress has been shown to produce an inflammatory reaction,20 which has led researchers to suggest that it is in particular the experience of acute stress, such as present in panic disorders, causing the high levels of inflammation in anxiety.18 On the other hand, chronic stress may initiate changes in the hypothalamic–pituitary–adrenal (HPA) axis and the immune system, which in turn can trigger depression as well as anxiety.21 These pathways are not independent as the HPA-axis and the immune system are closely linked. Although the HPA axis in normal situations should temper inflammatory reactions, prolonged hyperactivity of the HPA axis could result in blunted anti-inflammatory responses to glucocorticoids resulting in increased inflammation.22, 23 Likewise, it can be hypothesized that immune changes associated with chronic disease and aging,24 could induce similar anxiety-enhancing effects. Although several mechanisms might explain an association between inflammation and anxiety disorders, it can be expected that immune dysregulation is not a general phenomenon in anxiety disorders, but might be restricted to specific subgroups. Whether this anxiety subgroup is defined by the type of disorder, the severity or duration of the disorder, the co-morbidity with depression, or its age of onset, is yet to be examined.

 

The present study investigates the association between several common anxiety disorders (generalized anxiety disorder, social phobia, panic disorder, agoraphobia) and heightened inflammation (CRP, interleukin (IL)-6, tumor necrosis factor (TNF)-α) in a large sample of persons with current and remitted anxiety disorders and healthy controls. In addition, it will be examined whether specific anxiety characteristics (severity, duration, age of onset, subtype, depression co-morbidity) further discriminate those anxiety patients with elevated inflammation.

 

Subjects and Methods

 

Sample

 

The Netherlands Study of Depression and Anxiety (NESDA) includes 2981 persons with and without depressive and anxiety disorders, aged 18–65 years at the baseline assessment in 2004–2007. Participants were recruited from the community (19%), general practice (54%) and secondary mental health care (27%) in order to reflect the broad range and developmental trajectory of psychopathology. Persons with insufficient command of the Dutch language or a primary clinical diagnosis of bipolar disorder, obsessive compulsive disorder, severe substance use disorder, psychotic disorder or organic psychiatric disorder, as reported by themselves or their mental health practitioner, were excluded. A detailed description of the NESDA study design and sampling procedures can be found elsewhere.25 The research protocol was approved by the ethics committee of participating universities and after complete description of the study all respondents provided written informed consent.

 

During the baseline interview, the presence of anxiety disorder (generalized anxiety disorder, social phobia, panic disorder, agoraphobia) and depressive disorder (major depressive disorder, dysthymia) was established using the Composite Interview Diagnostic Instrument (CIDI) according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria.26 The CIDI is a highly reliable and valid instrument for assessing depressive and anxiety disorders27 and was administered by specially trained research staff. In addition, the severity of anxiety was measured in all participants using the 21-item self-report Beck Anxiety Inventory.28 For the present analyses, we selected persons with a current (that is, past 6 months) or remitted (lifetime, but not current) anxiety disorder and healthy controls. Healthy controls had no lifetime anxiety or depressive disorder and a Beck Anxiety Inventory score below 10, as a score of 10 or above indicates mild anxiety.29 Persons with anxiety disorders were allowed to have a co-morbid depression. Of these 2342 persons, 54 were excluded due to missing information on inflammatory markers, leaving a sample of 2288 persons for the present study. Persons with missing data on inflammation were less often female (55.6 versus 66.9%, P=0.08), but did not differ from included persons in terms of age, years of education and the presence of anxiety disorder.

 

Anxiety Characteristics

 

Next to subtype of CIDI anxiety disorder diagnosis (generalized anxiety disorder, social phobia, panic disorder, agoraphobia), anxiety characteristics included anxiety symptoms severity as measured by the Beck Anxiety Inventory, and anxiety symptoms duration, using the Life Chart Interview (LCI).30 The LCI uses a calendar method to determine life events during the past 4 years to refresh memory after which the presence of anxiety and avoidance symptoms during that period is assessed. From this, the per cent of time patients reported anxiety symptoms was computed. The LCI has been used by other large cohort studies31 and event history calendars such as the LCI have been suggested a natural method of choice for retrospective data collection.32 To be able to test whether inflammation was in particular associated with anxiety disorders with a later onset, as we had found for depression,33 age of anxiety onset was derived from the CIDI interview. Last, the presence of a current co-morbid depressive disorder (major depressive disorder, dysthymia) was taken from the CIDI to check whether a possible inflammation–anxiety association was independent of co-morbid depression.

 

Inflammatory Markers

 

Markers of inflammation were assessed at the baseline NESDA measurement and included CRP, IL-6 and TNF-α. Fasting blood samples of NESDA participants were obtained in the morning between 0800 and 0900 hours and kept frozen at −80 °C. CRP and IL-6 were assayed at the Clinical Chemistry Department of the VU University Medical Center. High-sensitivity plasma levels of CRP were measured in duplicate by an in-house ELISA based on purified protein and polyclonal anti-CRP antibodies (Dako, Glostrup, Denmark). Intra- and inter-assay coefficients of variation were 5% and 10%, respectively. Plasma IL-6 levels were measured in duplicate by a high sensitivity ELISA (PeliKine CompactTM ELISA, Sanquin, Amsterdam, The Netherlands). Intra- and inter-assay coefficients of variation were 8% and 12%, respectively. Plasma TNF-α levels were assayed in duplicate at Good Biomarker Science, Leiden, The Netherlands, using a high-sensitivity solid phase ELISA (Quantikine® HS Human TNF-α Immunoassay, R&D systems, Minneapolis, MN, USA). Intra- and inter-assay coefficients of variation were 10% and 15%, respectively.

 

Covariates

 

Sociodemographic characteristics included sex, age and years of education. As lifestyle characteristics can be associated with both anxiety and inflammation, smoking status (never, former, current), alcohol intake (<1, 1–14 (women)/1–21 (men), >14 (women)/>21 (men) drinks per week), physical activity (measured with the International Physical Activity Questionnaire34 in MET-minutes (ratio of energy expenditure during activity compared with rest times the number of minutes performing the activity) per week) and body mass index (weight in kilograms divided by height in meters squared) were assessed. In addition, several disease-related covariates were taken into account including the presence of cardiovascular disease (assessed by self-report supported by appropriate medication use (see Vogelzangs et al.6 for detailed description)), the presence of diabetes (fasting plasma glucose level ⩾7.0 mmol l−1 or use of anti-diabetic medication (ATC code A10)) and the number of other self-reported chronic diseases for which persons received treatment (including lung disease, osteoarthritis or rheumatic disease, cancer, ulcer, intestinal problem, liver disease, epilepsy and thyroid gland disease). Medication use was assessed based on drug container inspection of all drugs used in the past month and classified according to the World Health Organization Anatomical Therapeutic Chemical classification.35 Statin use (C10AA, C10B) and use of systemic anti-inflammatory medication (M01A, M01B, A07EB, A07EC) were assessed. Antidepressant medication included regular use (>50% of the time) of selective serotonin reuptake inhibitors (SSRI; N06AB), serotonin-norepinephrine reuptake inhibitors (SNRI; N06AX16, N06AX21), tricyclic antidepressants (TCA; N06AA) and tetracyclic antidepressants (TeCA; N06AX03, N06AX05, N06AX11).

 

Statistical Analyses

 

Baseline characteristics were compared between men and women using χ2 test for dichotomous and categorical variables, independent samples t-test for continuous variables, and Mann–Whitney U-test for inflammatory markers. For subsequent analyses, CRP, IL-6 and TNF-α were ln-transformed to normalize distributions, but back-transformed values are presented to enhance interpretation. Associations between anxiety disorders and inflammatory markers were examined using analyses of (co)variance, and (adjusted) means across anxiety groups (no, remitted, current) are presented. To take the effects of potential confounding factors into account, three different models were tested: unadjusted, adjusted for sociodemographics (sex, age, education) and additionally adjusted for lifestyle and disease (smoking status, alcohol intake, physical activity, body mass index, cardiovascular disease, diabetes, number of other chronic diseases, statins, anti-inflammatory medication). As depression has been reported to differentially affect inflammation in men and women,33 a sex-interaction for anxiety disorders is plausible. Therefore, we tested sex-interactions by including a sex × anxiety disorder status interaction term. When present, analyses were repeated sex stratified.

 

To test whether specific anxiety characteristics were related to elevated inflammation levels, we performed linear regression analyses with inflammatory markers as the outcome for each anxiety characteristic (severity, duration, age of onset, subtype, depression co-morbidity) within the sample of persons with a current anxiety disorder.

 

Dr-Jimenez_White-Coat_01.png

Dr. Alex Jimenez’s Insight

Anxiety is a common term which is often used to refer to situational stress or to describe momentary tenseness, however, for individuals living with an anxiety disorder, the symptoms associated with this mental health issue can be debilitating. Anxiety can be caused by a wide variety of factors, including depression and chronic pain, however, research studies have started to hypothesize that another common factor may be the true source as to why some people develop anxiety while other don’t: inflammation. The connection between anxiety and inflammation, as well as depression and inflammation, is becoming increasingly understood. Anxiety isn’t likely caused by inflammation alone, but, measuring inflammatory levels in the body could help determine the best treatment approach for a variety of anxiety disorders and for underlying health issues most commonly associated with inflammation, such as chronic pain.

 

Results

 

Mean age of the study sample was 41.8 (s.d.=13.1) years and 66.9% were women. Baseline characteristics of the total sample and for men and women separately are shown in Table 1. Women were younger, more often non-drinkers, had a lower body mass index, less often cardiovascular disease or diabetes and less often used statins than men. In addition, women had higher levels of CRP than men. All covariates were associated with at least one of the inflammation markers, which has been presented elsewhere.33 Pearson’s correlations between inflammatory markers were modest (CRP–IL-6: r=0.31; CRP–TNF-α: r=0.13; IL-6–TNF-α: r=0.12; all P<0.001).

 

Table 1 Baseline Characteristics

 

Table 2 shows (adjusted) mean inflammation levels across anxiety groups (controls, remitted, current) based on analyses of (co)variance. In the total sample, higher CRP levels were found in persons with a current anxiety disorder compared with controls in unadjusted analyses (1.36 (s.e.=1.04) versus 1.11 (s.e.=1.05) mg l−1, P=0.001), but after adjustment, there were no associations between anxiety disorders and any of the inflammation markers. However, a significant sex × anxiety disorder interaction was found for CRP (remitted: P=0.57; current: P=0.002). Stratified analyses for CRP showed that even after full adjustment for lifestyle and disease, men with current anxiety disorders had higher levels of CRP compared with controls (1.18 (s.e.=1.05) versus 0.98 (s.e.=1.07) mg l−1, P=0.04, Cohen’s d=0.18). In women, anxiety disorders were not significantly associated with CRP. No sex interactions were found for IL-6 (remitted: P=0.47; current: P=0.40) or TNF-α (remitted: P=0.92; current: P=0.87). As we have previously reported associations between inflammatory levels and antidepressant use within currently depressed persons,33 we checked the influence of antidepressant use on our current results. Higher levels of CRP were found in TCA/TeCA users within our present sample of persons with current anxiety disorders (N=1273; P=0.001). To examine whether the finding of elevated CRP in currently anxious men was independent of TCA/TeCA use, we excluded all men using TCA/TeCA (N=36). Results remained similar, although no longer significant (men with current anxiety disorders versus controls: 1.13 (s.e.=1.05) versus 0.97 (s.e.=1.07) mg l−1, P=0.08, Cohen’s d=0.15). In addition, to reduce the possible confounding effects of acute illness on inflammatory levels at the time of blood draw, all persons who reported having had a cold or fever in the week before blood draw were excluded (N=645), but findings remained alike (men with current anxiety disorders versus controls: 1.09 (s.e.=1.06) versus 0.91 (s.e.=1.07) mg l−1, P=0.06, Cohen’s d=0.19).

 

Table 2 Adjusted Mean Marker Levels

 

To investigate whether specific anxiety characteristics (severity, duration, age of onset, subtype, depression co-morbidity) were associated with inflammation, linear regression analyses were performed within the subgroup of persons with current anxiety disorders (N=1273; Table 3). Anxiety severity and duration did not correlate with inflammation. Later age of anxiety disorder onset was associated with elevated CRP levels (β=0.053, P=0.05), even after additional adjustment for TCA/TeCA use (β=0.053, P=0.05). Persons with social phobia had lower levels of CRP (β=−0.053, P=0.04) and IL-6 (β=−0.052, P=0.05) compared with persons with other types of anxiety disorders. The association between social phobia and IL-6 appeared to be specific for women (β=−0.089, P=0.007), but not men (β=0.025, P=0.61; P sex-interaction=0.05). Co-morbid depressive disorder did not further differentiate anxious persons with elevated inflammation.

 

Table 3 Association of Characteristics

 

To further illustrate the findings with regard to age of onset, we constructed five age of anxiety disorder onset groups (<20, 20–30, 30–40, 40–50, ⩾50). Figure 1 presents adjusted means of back-transformed CRP levels across controls and age of onset groups based on analysis of covariance. CRP levels were only increased in persons with an age of onset after 50 years (1.95 (s.e.=1.18) versus 1.27 (s.e.=1.05) mg l−1 in controls, P=0.01, Cohen’s d=0.37). For comparison, adjusted mean CRP levels for persons with cardiovascular disease were 1.62 (s.e=1.11), illustrating the clinical relevance of this finding. Excluding persons reporting having had a cold or fever in the week before blood draw (N=513), yielded similar findings (age of onset after 50 years versus controls: 1.73 (s.e.=1.20) versus 1.18 (s.e.=1.05) mg l−1, P=0.04, Cohen’s d=0.35). Results were also similar when the analysis of Figure 1 was restricted to the sample of persons aged 50 years or above (N=589; age of onset after 50 years versus controls: 2.05 (s.e.=1.16) versus 1.35 (s.e.=1.08) mg l−1, P=0.01, Cohen’s d=0.40), underlining that higher CRP in those with an age of onset of 50 years or above was not due to the higher age itself in these persons. Last, in a post-hoc analysis, we directly compared CRP levels between persons with a late versus early onset of anxiety disorder at a cutoff of 50 years, and found significantly higher CRP levels in the late onset group (1.91 (s.e.=1.19) versus 1.35 (s.e.=1.03) mg l−1, P=0.05, Cohen’s d=0.30).

 

Figure 1 Adjusted Mean CRP Levels

 

Discussion

 

The current study is one of the first and the largest to date to examine the association between anxiety disorders and inflammation. The results show that men with a current anxiety disorder have somewhat increased levels of CRP, even after taking a large set of lifestyle and disease factors into account. Elevated levels of CRP were in particular found in those persons with a late onset of the anxiety disorder.

 

Our results are in line with the few previous studies examining the relationship between anxiety symptoms or disorders with inflammation. Available evidence until now was limited to assessing anxiety symptoms in the general population,14, 15 confined to specific anxiety disorders in small clinical samples16, 17, 18 or in a heart disease population.19 Our study adds to the literature by showing that elevated CRP levels can be found among several common anxiety disorders in a relatively large cohort of anxious persons and controls, specifically in those with a later onset of the anxiety disorder. CRP levels were in particular elevated among men with anxiety disorders, which is in line with the large-scale study by Liukkonen et al.,15 which showed an association between anxiety symptoms and CRP only in men. In contrast, Pitsavos et al.14 found associations between an anxiety symptoms score and CRP levels in both men and women. Persons included in the study by Pitsavos et al. were much older (18–89 years; mean age 45 years) than those in the study by Liukkonen et al. (all 31 years old), and slightly older than those in the present study (18–65 years; mean age 42 years). Perhaps sex differences become less clear with increasing age, as a result of hormonal changes across the lifespan of women, which affect inflammation levels.36 This could be in line with our finding that CRP levels were elevated in both men and women with a late onset of anxiety disorders.

 

Our findings with respect to anxiety disorders are also very comparable to our earlier findings regarding depressive disorders and inflammation.33 In that study, we found elevated inflammation, specifically CRP, in depressed men, especially among those with a later depression onset. The effect sizes for CRP in men with a current disorder are also comparable for anxiety (Cohen’s d=0.18) and depressive (Cohen’s d=0.21) disorders. A trend for association with IL-6, which was found for current depressive disorders in men, was not found for current anxiety disorders. Of note is that in persons with an anxiety disorder, a co-morbid depressive disorder was not associated with higher inflammation levels, suggesting that the effects found for anxiety disorders are independent of depression.

 

In line with our previous findings for current depressive disorders,33 CRP levels were in particular elevated among persons with a later onset of anxiety disorders. In contrast, characteristics that are more often associated with an early age of onset, such as higher severity and longer duration were not associated with increased inflammation. Also, in our sample, women had an earlier age of anxiety disorder onset than men, possibly contributing to the lack of an overall association between anxiety disorders and inflammation in women. Furthermore, we found that CRP levels were lowest among persons with social phobia when compared with other anxiety disorders, in particular in women. Social phobia has been reported to have a much earlier age of onset compared with generalized anxiety disorder or panic disorder,37 which was confirmed in our sample (16.6 versus 25.9 years, P<0.001). To our knowledge, no other study has yet examined the association between social phobia and inflammation. In our study, only nine persons with social phobia had an disorder onset at or after 50 years. Therefore, low inflammation levels in persons with social phobia cannot explain our findings for elevated CRP levels in persons with an age of anxiety disorder onset after 50 years. A recent study by Copeland et al.38 showed that, after taking health-related behaviors into account, generalized anxiety disorder was not associated with elevated CRP levels among children and adolescents. These findings argue against the idea that the inflammation–anxiety association is merely a result of acute stress experienced in anxiety disorders. Although we cannot make inferences about etiology based on our cross-sectional analyses, our current findings are in line with the growing evidence suggesting a distinct etiology involving vascular/metabolic/inflammatory factors in depression or anxiety disorders with an onset later in life.39, 40, 41, 42 Possibly, accumulating psychological and physical stress across the life-span might induce immunological changes24 that eventually results in depression and anxiety.

 

In our previous report,33 we had found differences in inflammation levels among different classes of antidepressant medication use, which was confirmed for higher CRP in TCA/TeCA users within our present sample of persons with current anxiety disorders. Excluding persons using TCA or TeCA, resulted in a slightly weaker effect size for the association between current anxiety disorder and CRP in men. This might suggest that the elevated CRP levels in men with current anxiety disorders are for some part due to use of TCA/TeCA. On the other hand, persons using TCA/TeCA might represent the more severe cases of anxiety disorders, in which case exclusion of these persons leads to an underestimation of the association. Adjustment for TCA/TeCA use had no effect on our findings for age of anxiety disorder onset, suggesting that late-onset anxiety disorders are independently associated with higher levels of CRP.

 

What are the clinical implications of our findings? First, our finding of increased CRP levels in particularly those with a late onset of the anxiety disorder might implicate the existence of a specific late-onset anxiety subtype with a distinct etiology. As we have found similar results for depression33 and because depression and anxiety are highly co-morbid disorders,11 this might suggest that depression and anxiety with a late onset share a similar etiology and represent one particular group of disorders, which might be more distinct from other depressive or anxiety disorders, which present earlier in life. As we can only speculate on etiology based on our cross-sectional research, longitudinal research is needed to validate the existence of an etiologically distinct late-onset subtype. Second, if confirmed, a distinct etiology for late-onset disorders implicates different treatment strategies for this subgroup. Perhaps anti-inflammatory medication or lifestyle interventions, such as exercise, for which (some) evidence exists that they normalize immune and metabolic dysregulation,43 as well as improve depressive symptoms to some degree,44, 45 could be beneficial in persons with late onset anxiety disorders as well.

 

Our study has some important strengths such as a large sample size, assessment of multiple inflammatory markers, clinical diagnoses of several anxiety disorders, adequate adjustment for potential confounders and the ability to examine the role of anxiety characteristics. However, some limitations need to be acknowledged. As our data are cross-sectional, we cannot make any inferences about the direction of the association. Also, although we adjusted for a large set of possible confounding factors, unmeasured poor lifestyle behaviors or health factors may be the explaining link between inflammation and anxiety disorders. For instance, subclinical cardiovascular disease could possibly precede both inflammation and anxiety. On the other hand, subclinical disease may be one pathway of how inflammation leads to anxiety in later life. Longitudinal studies are needed to investigate whether immune dysregulation is a precursor or the result of anxiety, or whether this relationship is bidirectional. Further, like most other studies, we assessed circulating levels of inflammatory markers, which show a high degree of intra-individual variation that could explain the rather modest overall associations between anxiety disorders and inflammation in our study.

 

In conclusion, our results show that low-grade systemic inflammation is present in men with anxiety disorders. Elevated inflammation is in particular found in both men and women with the onset of anxiety disorder later in life. Longitudinal studies are needed to confirm inflammation as an etiological factor in anxiety disorders with a late-life onset, followed by intervention trials investigating new treatment strategies (for example, anti-inflammatory medication, lifestyle interventions) for this subset of persons with late-onset anxiety.

 

Acknowledgments

 

The infrastructure for the NESDA study (http://www.nesda.nl) is funded through the Geestkracht program of the Netherlands Organisation for Health Research and Development (Zon-Mw, grant number 10-000-1002) and is supported by participating universities and mental health care organizations (VU University Medical Center, GGZ inGeest, Arkin, Leiden University Medical Center, GGZ Rivierduinen, University Medical Center Groningen, Lentis, GGZ Friesland, GGZ Drenthe, Institute for Quality of Health Care (IQ Healthcare), the Netherlands Institute for Health Services Research (NIVEL) and the Netherlands Institute of Mental Health and Addiction (Trimbos)). NV was supported through a fellowship from the EMGO Institute for Health and Care Research and BP through a VICI grant (NWO grant g1811602). Assaying of inflammatory markers was supported by the Neuroscience Campus Amsterdam.

 

Notes

 

The authors declare no conflict of interest.

 

Supporting the Endocannabinoid System | El Paso, TX Chiropractor

 

Beyond CBD – Supporting the Entire Endocannabinoid System

 

Every day, more and more health-conscious consumers are starting to take great interest in nutritional supplements that encourage the proper function of the endocannabinoid system, or ECS. Although marijuana and substances derived from or related to marijuana were believed to be the only options to achieve this effect, the focus in the consumer market has largely shifted to a single chemical: cannabidiol.

 

What’s CBD?

 

Cannabidiol, commonly known as CBD, is a chemical found in marijuana and in hemp which does interact with the ECS. CBD is just one of a wide group of chemicals known as phytocannabinoids. Cannabidiol has turned into a well-known phytocannabinoid because it is being researched to turn into a new medication and also the benefits demonstrated by CBD have created a lot of attention in this compound.

 

What Can CBD Do?

 

Although CBD does perform multiple actions within the human body, its own best-known function in the ECS, or endocannabinoid system, is in its potential to inhibit the activity of the enzyme called fatty acid amide hydrolase, or FAAH. FAAH breaks down anandamide, among the body’s endogenous cannabinoids, which is known to bind to the ECS’s CB1 receptor. The ECS’s CB1 receptor, primarily found in the brain, is the exact same receptor which THC, or tetrahydrocannabinol, binds to. In other words, anandamide, often referred to as “the bliss molecule”, is the human body’s natural THC.

 

Significantly, however, whereas THC could have negative effects, such as triggering feelings of anxiety, mild hallucinations, dizziness, rapid heart rate, slowed reaction times, and food cravings, the anandamide made naturally by the body appears to exert positive effects on mood, memory, brain function and pain. Because anandamide is normally rapidly broken up by FAAH and because CBD modulates FAAH, Cannabidiol’s primary importance is in the way it can maintain anandamide levels, thus enhancing anandamide’s beneficial impact in the ECS. CBD also binds directly to CB1 and CB2 receptors and has a selection of activity outside of the ECS which can result in its many health benefits.

 

CBD is a Drug According to the FDA

 

Because CBD is comparatively safe, lacks the unwanted side effects of THC, and may be easily derived from hemp instead of marijuana, the natural products industry was flooded with products labeled as CBD. However, before this recent phenomenon, a British pharmaceutical company began studying the merits of CBD as an alternate to the drugs and/or medications being utilized to treat resistant childhood epilepsy.

 

This company, GW Pharmaceuticals (dba Greenwich Biosciences) began pre-clinical operations on CBD in 2007 and contains an investigational new drug called Epidiolex® in late stage clinical trials.

 

In multiple warning letters in 2017 sent to a number of businesses, the FDA noted ,”If an article, such as CBD, has been approved for investigation as a new drug and/or medication for which substantial clinical investigations have been instituted and for which the existence of such investigations have been made public, then products containing that chemical are outside the definition of a dietary supplement” Since the investigational work completed on CBD as a drug predates the promotion of CBD as a dietary supplement, products containing purified CBD or enriched with CBD are considered by the FDA to be medication and not dietary supplements.

 

Why Support the Entire ECS?

 

The ECS is not just a bodily system which completes a single function, as a matter of fact it’s far from it. ECS receptors are widely dispersed throughout the entire body. CBD is an isolated molecule which acts primarily on just a single component of the ECS; i.e., it inhibits the degrading enzyme FAAH, thus allowing the anandamide naturally produced by your endocannabinoid system to possess higher action. But what about the rest of the ECS?

 

The ECS has at least two major receptors, CB1 and CB2 receptors. And along with anandamide, humans also produce an endocannabinoid called 2-archidonoyl glycerol, or 2-AG, which can be degraded by the enzyme monoacylglycerol lipase, or MAGL. If our intention is to support and nourish the whole ECS, then focusing on a single molecule like CBD that only works on one portion of the ECS might not be the best approach.

 

Hemp includes heaps of active molecules, including a range of phytocannabinoids. Some such as cannabigerol, or CBG, bind weakly to the CB1 and CB2 receptors. Both CBG and cannabichromene, or CBC, may also help maintain wholesome anandamide levels. The phytocannabinoid beta-caryophyllene, or BCP, that is found in plants like black pepper and clove, binds to the CB2 receptor, which supports the actions of 2AG. Other natural plant compounds, particularly specific terpenoids, have functions which are complementary to that of phytocannabinoids.

 

The “Entourage” Impact

 

Although isolated CBD does have a part in overall health and wellness, cannabidiol is not anywhere near the entire process for encouraging the ECS. By using a whole hemp stalk infusion combined with hops, pepper, clove and rosemary that include naturally occurring complementary compounds, hemp oil nourishes the whole ECS, giving a holistic approach to a system that’s often neglected and out of equilibrium in today’s stressful world.

 

Hemp oil nourishes the entire ECS, giving a holistic approach to a system that’s frequently ignored and out of equilibrium in today’s stressful world. Scientists who research the ECS refer to the approach as the”entourage” effect, and several top researchers believe this approach to be extremely effective in keeping the health and tone of the valuable endocannabinoid system as well as controlling the symptoms of inflammation and anxiety in the human body.

 

In conclusion, anxiety is one of the most common mental health disorders in the United States. This debilitating health issue can be caused by a variety of factors, however, many research studies have started to demonstrate a connection between anxiety disorders and brain inflammation. According to the article above, stress has been shown to produce an inflammatory reaction, which has led researchers to suggest that anxiety may be causing high levels of inflammation. The outcome measures of te cohort study found that low-grade inflammation is present in individuals with anxiety disorders. Further research studies are still required to confirm the connection between anxiety and inflammation. Furthermore, supporting the function of the endocannabinoid system, or ECS, with the use of CBD or cannabidiol, has been found to have many health benefits, including helping with inflammation and anxiety.  Information referenced from the National Center for Biotechnology Information (NCBI). The scope of our information is limited to chiropractic as well as to spinal injuries and conditions. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at 915-850-0900 .

 

Curated by Dr. Alex Jimenez

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Additional Topics: Back Pain

Back pain is one of the most prevalent causes for disability and missed days at work worldwide. As a matter of fact, back pain has been attributed as the second most common reason for doctor office visits, outnumbered only by upper-respiratory infections. Approximately 80 percent of the population will experience some type of back pain at least once throughout their life. The spine is a complex structure made up of bones, joints, ligaments and muscles, among other soft tissues. Because of this, injuries and/or aggravated conditions, such as herniated discs, can eventually lead to symptoms of back pain. Sports injuries or automobile accident injuries are often the most frequent cause of back pain, however, sometimes the simplest of movements can have painful results. Fortunately, alternative treatment options, such as chiropractic care, can help ease back pain through the use of spinal adjustments and manual manipulations, ultimately improving pain relief.

 

 

 

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EXTRA IMPORTANT TOPIC: Low Back Pain Management

 

MORE TOPICS: EXTRA EXTRA: Chronic Pain & Treatments

 

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The Connection Between Inflammation and Depression

The Connection Between Inflammation and Depression

One standard hypothesis of depression is that individuals who are depressed have a lack in monoamine receptors within the body, which in turn leads to reduced levels of neurotransmitters, such as serotonin and norephinephrine, in the brain. But growing evidence supports that at least some kinds of depression might also be linked to continuing low-grade inflammation in the body.

Previous research studies have linked depression with higher level of inflammatory markers when compared with people who aren’t depressed. When individuals are given pro-inflammatory cytokines, they report experiencing more symptoms of depression and anxiety. Chronically high levels of inflammation due to health issues, including chronic pain conditions, are also associated with high rates of depression. Even brain imaging of patients with depression show their brain scans have improved neuroinflammation. If your body is in an inflammatory state, fighting off the common cold or influenza, you can experience symptoms overlapping with depression, including, interrupted sleep, depressed mood, fatigue, foggy-headedness and impaired concentration.

A new study published in The Journal of Clinical Psychiatry supports the assumption that an increase in inflammation might play a role in depression. The huge study analyzed data from 14,275 people who have been interviewed between 2007 and 2012 using the Patient Health Questionnaire, or PHQ-9, to screen for depression and had blood samples drawn. They found that people who had depression had 46 percent greater levels of C-reactive protein, or CRP, a marker of inflammatory disease, in their own blood samples. The research study was just able to establish an association between inflammation and depression but not causation, even though it confirms the association of depression with high levels of inflammation as measured through CRP.

The theory that depression might be viewed as a psychoneuroimmunological disorder may also help explain why attempts to reduce chronic inflammation in the body also enhances and helps prevent depression. The purpose of the article below is to demonstrate as well as thoroughly discuss the role of inflammation in depression. Furthermore, the article will describe the evolutionary imperative to the modern treatment target, including a discussion of phytocannabinoids and their association with the treatment of a variety of health issues, including chronic pain symptoms.

The Role of Inflammation in Depression: from Evolutionary Imperative to Modern Treatment Target

Abstract

Crosstalk between inflammatory pathways and neurocircuits in the brain can lead to behavioural responses, such as avoidance and alarm, that are likely to have provided early humans with an evolutionary advantage in their interactions with pathogens and predators. However, in modern times, such interactions between inflammation and the brain appear to drive the development of depression and may contribute to non-responsiveness to current antidepressant therapies. Recent data have elucidated the mechanisms by which the innate and adaptive immune systems interact with neurotransmitters and neurocircuits to influence the risk for depression. Here, we detail our current understanding of these pathways and discuss the therapeutic potential of targeting the immune system to treat depression.

Introduction

Depression is a devastating disorder, afflicting up to 10% of the adult population in the United States and representing one of the leading causes of disability worldwide1. Although effective treatments are available, approximately one third of all patients with depression fail to respond to conventional antidepressant therapies2, further contributing to the global burden of the disease. Accordingly, there is a pressing need for new conceptual frameworks for understanding the development of depression to develop better treatments. In this Review, we outline emerging data that point to the immune system — and, in particular, the inflammatory response — as a potentially important contributor to the pathophysiology of depression. We first consider the origins of this notion from an evolutionary perspective, examining the advantages of depressive behaviours in the context of host immune responses to pathogens, predators and conspecifics in ancestral environments. The pivotal role of psychosocial stress in the modern world are then examined, highlighting inflammasome activation and immune cell trafficking as novel mechanisms by which stress-induced inflammatory signals can be transmitted to the brain. Neurotransmitters and neurocircuits that are targets of the inflammatory response are also explored followed by an examination of brain–immune interactions as risk and resilience factors for depression. Finally, these interactions are discussed as a foundation for a new era of therapeutics that target the immune system to treat depression, with a focus on how immunological biomarkers can be used to personalize care.

An Evolutionary Perspective

Data from humans and laboratory animals provide compelling evidence that stress-relevant neurocircuitry and immunity form an integrated system that evolved to protect organisms from a wide range of environmental threats. For example, in the context of a laboratory stressor that entails delivering a speech to a judgmental panel of supposed ‘behavioural experts’, subjects experience a classic ‘fight or flight’ response characterized by increases in heart rate and blood pressure as well as in cortisol and catecholamines. But something else happens within the body that demands a deeper explanation. The stressor activates key inflammatory pathways in peripheral blood mononuclear cells, including activation of the transcription factor nuclear factor–κB (NF-κB), and leads to marked increases in circulating levels of pro-inflammatory cytokines, such as interleukin-6 (IL-6)3,4. In essence, the body mounts an immune response not against a pathogen, but against a threat to the subject’s self-esteem. Moreover, individuals at high risk of developing depression (for example, those who have experienced early-life trauma) show increased inflammatory responses to such laboratory stressors compared with low-risk individuals3. Furthermore, the greater the inflammatory response to a psychosocial stressor, the more probable the subject is to develop depression over the ensuing months5. Two questions immediately present themselves: why should a stimulus devoid of any pathogen induce an inflammatory response, and why should this response promote the development of depression?

Pathogen Host Defense and Depression

No coherent answer to these questions is apparent if immunity is viewed as merely another physiological system within the body. However, when seen against the back-drop of millions of years of co-evolution between mammals and the world of microorganisms and parasites, the human inflammatory bias exposed by laboratory stressors and reflected in the association between immune activation and depression not only makes imminent adaptive sense but also provides insight into a paradox deep within the heart of depression itself; namely, why are the genetic alleles that are most frequently associated with depression so common in the modern gene pool6 (FIG. 1)

Figure 1 Evolutionary Legacy of an Inflammatory Bias | El Paso, TX Chiropractor

Figure 1: Evolutionary legacy of an inflammatory bias. Early evolutionary pressures derived from human interactions with pathogens, predators and human conspecifics (such as rivals) resulted in an inflammatory bias that included an integrated suite of immunological and behavioural responses that conserved energy for fighting infection and healing wounds, while maintaining vigilance against attack. This inflammatory bias is believed to have been held in check during much of human evolution by exposure to minimally pathogenic, tolerogenic organisms in traditional (that is, rural) environments that engendered immunological responses characterized by the induction of regulatory T (TReg) cells, regulatory B (BReg) cells and immunoregulatory M2 macrophages as well as the production of the anti-inflammatory cytokines interleukin-10 (IL-10) and transforming growth factor-β (TGFβ). In modern times, sanitized urban environments of more developed societies are rife with psychological challenges but generally lacking in the types of infectious challenges that were primary sources of morbidity and mortality across most of human evolution. In the absence of traditional immunological checks and balances, the psychological challenges of the modern world instigate ancestral immunological and behavioural repertoires that represent a decided liability, such as high rates of various inflammation-related disorders including depression.

Most adaptive theories of depression have focused on the potential benefits of depressive symptoms for relationships with other humans7. However, recent models have shifted the focus away from relationships with people, to relationships — both detrimental and beneficial — with pathogens6,8. These theories, which are supported by converging evidence (BOX 1), posit that modern humans have inherited a genomic bias towards inflammation because this response — and the depressive symptoms it promotes — enhanced host survival and reproduction in the highly pathogenic environments in which humans evolved6. From this theoretical perspective, at least some of the human vulnerability to depression evolved out of a behavioural repertoire — often referred to as ‘sickness behaviour’ — which promoted host survival in the face of infection. Indeed, it has been hypothesized that the social avoidance and anhedonia characteristic of depression serve to shunt energy resources to fighting infection and wound healing, whereas the hypervigilance characteristic of anxiety disorders, commonly comorbid with depression, subserves protection from attack and subsequent pathogen exposure6,9. Even psychological stress can be understood from this theoretical perspective, given that the vast majority of stressors faced by mammals over evolutionary time boiled down to risks inherent in hunting, being hunted or competing for reproductive access or status. In all of these circumstances, the risk of pathogen invasion — and subsequent death from infection — was greatly increased as a result of wounding. In ancestral environments, the association between stress perception and risk of subsequent wounding was reliable enough that evolution favoured organisms that prepotently activated inflammatory systems in response to a wide array of environmental threats and challenges (including psychosocial stressors), even if this activation was often a ‘false alarm’ (REF. 6).

Pathogen Host Defense Hypothesis of Depression

Several lines of evidence support the notion that the evolution and persistence of depression risk alleles and depressive symptoms in human populations are based on their relevance to ‘pathogen host defence’. This evidence includes:

  • Until recently, approximately 50% of humans died from infectious causes before adulthood, thereby providing strong selective pressure for genetic alleles that enhance host defence124.
  • As a result of strong selective pressure, microbial interactions have been a primary driver of human evolution125.
  • Patterns of inflammatory activation associated with depression promote survival in highly pathogenic environments while increasing mortality in sanitary conditions common in the developed world126.
  • The best replicated risk alleles for depression have pro-inflammatory and/or anti-pathogen protective effects or have been implicated in social behaviours that are likely to reduce pathogen exposure6.
  • Environmental risk factors for the development of depression (that is, psychosocial stress, early life adversity, obesity and processed-food diet) are uniformly pro-inflammatory13.
  • Exposure to pro-inflammatory cytokines produces a sickness syndrome with symptoms that overlap considerably with those seen in depression and that can be ameliorated by treatment with antidepressants23. In addition, the onset of depression is often mistaken with development of sickness, and symptoms
  • associated with infections are often mistaken with the onset of depression127.
  • Chronic cytokine exposure produces a combination of withdrawal and/or energy conservation, anxiety and/or hypervigilance behaviours and emotions that commonly coexist in depression6,9.
  • Symptoms shared by depression and sickness behaviour — such as hyperthermia and reduced iron availability — that lack any conceivable social value have potent anti-pathogen effects6.

The ‘pathogen host defence’ hypothesis of depression may also provide insight into the twofold increase in depression in women compared to men, especially during the reproductive years10. Recent data indicate that women are more sensitive to the behavioural effects of inflammation, demonstrating greater increases in depressed mood than men following endotoxin exposure despite a similar magnitude in cytokine (IL-6 and tumour necrosis factor (TNF)) responses11. Women also exhibit a greater likelihood than men to develop depression in response to standardized doses of interferon-α (IFNα)12. By being more sensitive to inflammation-induced depressive symptoms, women may have benefited more from the protection provided by these symptoms in terms of fighting infection, healing wounds and avoiding subsequent pathogen exposure. Given the potentially negative impact of inflammation on reproductive success (for example, by reducing fertility and impairing lactation), the increase of depressive symptoms in women across evolutionary time may have given women of reproductive age an advantage in coping with and avoiding pathogens and the related inflammation, with increased depressive disorders being the ultimate trade-off in modern times.

Modern Exaggeration of the Inflammatory Bias

The prevalence of autoimmune, allergic and inflammatory diseases has markedly increased in the past 100 years, and rates of these conditions follow a similar upward trajectory in societies transitioning from traditional (that is, rural) to modern (that is, urban) ways of life13. Increasing evidence suggests that this pattern of widespread immune dysregulation may result from disruptions in our relationship and/or contact with a variety of co-evolved, non-lethal immunoregulatory microorganisms and parasites, especially commensals and symbiotes in the microbiotas of the gut, skin and nasal and oral cavities, that were ubiquitous in the natural environments in which humans evolved14. Although widely disparate, these organisms (often referred to as ‘old friends’) share a tendency to reduce inflammation and suppress effector immune cells through the induction of IL-10 and transforming growth factor-β (TGFβ) while promoting the development of anti-inflammatory immune cell populations, such as alternatively activated (also referred to as ‘M2’) macrophages and regulatory T (TReg) cells and regulatory B cells13,14 (FIG. 1). Owing to various cultural changes, including the loss of exposure to microbial diversity with the advent of sanitation practices, modern humans now lack this immunoregulatory input — especially during infancy and childhood. Consequently, we find ourselves in a condition of an exacerbated inflammatory bias, with the particular conditions afflicting any given individual largely the result of genetic predisposition and environmental (for example, psychosocial) exposures13,14, ultimately accounting for the high co-morbidity between depression and autoimmune, allergic and inflammatory disorders13,15.

Inflammation and Depression

Data supporting the role of inflammation in depression are extensive and include findings that span experimental paradigms. Patients with major depressive disorder exhibit all of the cardinal features of an inflammatory response, including increased expression of pro-inflammatory cytokines and their receptors and increased levels of acute-phase reactants, chemokines and soluble adhesion molecules in peripheral blood and cerebrospinal fluid (CSF)16,17. Peripheral blood gene expression profiles consistent with a pro-inflammatory ‘M1’ macrophage phenotype and an over-representation of IL-6, IL-8 and type I IFN-induced signalling pathways have also been described18–20. In addition, increased expression of a variety of innate immune genes and proteins, including IL-1β, IL-6, TNF, Toll-like receptor 3 (TLR3) and TLR4, has been found in post-mortem brain samples from suicide victims that had depression16,18,19,21. Meta-analyses of the literature conclude that peripheral blood IL-1β, IL-6, TNF and C-reactive protein (CRP) are the most reliable biomarkers of inflammation in patients with depression16. Polymorphisms in inflammatory cytokine genes, including those encoding IL-1β, TNF and CRP, have also been associated with depression and its response to treatment22. Moreover, other genes implicated in depression derived from meta-analyses of genome-wide association studies have been linked to the immune response and the response to pathogens including TNF6 (BOX 1). Administration of inflammatory cytokines (for example, IFNα) or their inducers (for example, endotoxin or typhoid vaccination) to otherwise non-depressed individuals causes symptoms of depression23–26. Furthermore, blockade of cytokines, such as TNF, or of inflammatory signalling pathway components, such as cyclooxygenase 2, has been shown to reduce depressive symptoms in patients with medical illnesses, including rheumatoid arthritis, psoriasis and cancer, as well as in patients with major depressive disorder27–29.

As the field has matured, it has become increasingly apparent that inflammatory markers are elevated not only in a subgroup of patients with depression30,31 but also in patients with other neuropsychiatric disorders including anxiety disorders and schizophrenia32,33. Moreover, as described below, it may be more accurate to characterize the impact of inflammation on behaviour as being associated not wholly with depression but with specific symptom dimensions across diagnoses that align with the Research Domain Criteria framework put forth by the National Institute of Mental Health (US Department of Health and Human Services). These symptoms, including positive and negative valence systems, relate to altered motivation and motor activity (anhedonia, fatigue and psychomotor impairment) and increased threat sensitivity (anxiety, arousal and alarm)34. Finally, inflammation has been associated with antidepressant treatment non-responsiveness9,32,35–37. For example, in a recent study, 45% of patients with non-response to conventional antidepressants exhibited a CRP >3 mg L−1 (REF. 30), which is considered indicative of a high level of inflammation on the basis of widely accepted cut-off points38. Of note, however, the percentage of patients with high CRP levels can vary as a function of the population being studied, with higher percentages in patients with depression and treatment resistance, childhood maltreatment, medical illnesses and metabolic syndrome.

Immune Pathways Involved in Depression

Inflammasomes: Stress in Translation

Exposure to psychosocial stress is one of the most robust and reproducible predictors of developing depression in humans and is the primary experimental pathway to depressive-like behaviour in laboratory animals. Thus, the observation that exposure to a psychosocial laboratory stressor can activate an inflammatory response in humans was a major breakthrough in linking inflammation to depression3,4. An important question for the field, however, is by what mechanism is stress translated into inflammation? Although considerable attention has been paid to stress-induced neuroendocrine pathways, including the hypothalamic–pituitary–adrenal (HPA) axis and the sympathetic nervous system (SNS), both of which have immunomodulatory functions39, recent focus has been shifted towards inflammasomes, which may represent a crucial immunological interface between stress and inflammation40 (FIG. 2). Inflammasomes are cytosolic protein complexes that form in myeloid cells in response to pathogenic microorganisms and non-pathogenic or ‘sterile’ stressors. Assembly of the inflammasome leads to activation of caspase 1, which then cleaves the precursor forms of IL-1β and IL-18 into the active cytokines41. Given the relatively sterile nature of psychosocial stress, primary interest has been directed towards understanding how inflammasome activation in depression may be triggered by endogenous damage-associated molecular patterns (DAMPs), including ATP, heat shock proteins (HSPs), uric acid, high mobility group box 1 (HMGB1) and a variety of molecules linked with oxidative stress. Indeed, all of these DAMPs are induced by the psychological and mixed (that is, psychological and physiological) stressors used in animal models of depression42; an effect that is in part mediated by stress-induced release of catecholamines43. Moreover, studies in laboratory animals indicate that chronic mild-stress activates the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome, which is well-known to respond to DAMPs44,45. Blockade of NLRP3 reverses stress-induced increases in IL-1β in the peripheral blood and brain, while also abrogating depressive-like behaviour in mice45. Interestingly, NLRP3 inflammasome upregulation and caspase-mediated cleavage of the glucocorticoid receptor can cause resistance to the effects of glucocorticoids, which are among the most potent anti-inflammatory hormones in the body46,47. Stress-induced glucocorticoid resistance is a well-characterized biological abnormality in patients with major depressive disorder and has been associated with increased inflammation48,49.

Figure 2 Transmitting Stress Induced Inflammatory Signals | El Paso, TX Chiropractor

Figure 2: Transmitting stress-induced inflammatory signals to the brain. In the context of psychosocial stress, catecholamines (such as noradrenaline) released by activated sympathetic nervous system fibres stimulate bone marrow production and the release of myeloid cells (for example, monocytes) that enter the periphery where they encounter stress-induced damage-associated molecular patterns (DAMPs), bacteria and bacterial products such as microbial-associated molecular patterns (MAMPs) leaked from the gut. These DAMPs and MAMPs subsequently activate inflammatory signalling pathways such as nuclear factor-κB (NF-κB) and the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome. Stimulation of NLRP3 in turn activates caspase 1, which leads to the production of mature interleukin-1β (IL-1β) and IL-18 while also cleaving the glucocorticoid receptor contributing to glucocorticoid resistance. Activation of NF-κB stimulates the release of other pro-inflammatory cytokines including tumour necrosis factor (TNF) and IL-6, which together with IL-1β and IL-18 can access the brain through humoral and neural routes. Psychosocial stress can also lead to the activation of microglia to a M1 pro-inflammatory phenotype, which release CC-chemokine ligand 2 (CCL2) that in turn attracts activated myeloid cells to the brain via a cellular route. Once in the brain, activated macrophages can perpetuate central inflammatory responses. ASC, apoptosis-associated speck-like protein containing a CARD; HMGB1, high mobility group box 1; HSP, heat shock protein; LPS, lipopolysaccharide; TLR, Toll-like receptor.

Supporting the potential role of the NLRP3 inflammasome in human depression are data demonstrating that increased expression of NLRP3 and caspase 1 in peripheral blood mononuclear cells of patients with depression is associated with increased blood concentrations of IL-1β and IL-18, which in turn correlate with depression severity19,50. In addition, DAMPs that are known to activate NLRP3 are increased in patients with mood disorders, with examples including HSPs, reactive oxygen species and other markers of oxidative stress such as xanthine oxidase, peroxides and F2-isoprostanes51–53. Finally, there is increasing interest in the potential role of the gut microbiome in mood regulation, which may be mediated in part by the inflammasomes54. Indeed, non-pathogenic commensal bacteria and derived microbial-associated molecular patterns (MAMPs) in the gut can leak into the peripheral circulation during stress and activate the inflammasomes55, a process mediated by the SNS and catecholamines56 (FIG. 2). Of note, stress-induced increases in IL-1β and IL-18 were attenuated by treating animals with antibiotics or neutralizing lipopolysaccharide (LPS), demonstrating the importance of the composition of the gut microbiome and gut permeability in stress-induced inflammatory responses55. Taken together, these data support the notion that the inflammasome may be a key immunological point of integration of stress-induced danger signals that ultimately drive inflammatory responses relevant to depression.

Transmitting Inflammatory Signals to the Brain

In addition to increased expression of innate immune cytokines and TLRs in post-mortem brain samples from suicide victims with depression, evidence of microglial and astroglial activation in several brain regions including frontal cortex, anterior cingulate cortex (ACC) and thalamus in post-mortem studies of patients with depression have been described57–59,60. Moreover, a well-controlled neuroimaging study using positron emission tomography (PET) and a radiolabelled tracer for the translocator protein (TSPO) — which is overexpressed in activated microglia, macrophages and astrocytes — revealed increased immune activation in the brains of patients with major depressive disorder compared with control subjects61. Of note, not all studies have revealed increased TSPO binding in patients with depression, possibly owing to effects of medication and/or a paucity of subjects with increased inflammation61,62. However, data from endotoxin administration to healthy volunteers indicates that radiolabelled TSPO ligands can readily identify cellular activation in several regions of the brain following a potent peripheral immune stimulus63.

Work from laboratory animal studies has elucidated several pathways through which inflammatory signals can be transmitted from the periphery to the brain (FIG. 2). These data support the idea that inflammatory responses in peripheral tissues may drive inflammation in the brain leading to depression. Much of the early work focused on how inflammatory cytokines, which are relatively large molecules, could cross the blood–brain barrier (BBB) and influence brain function64. Two major pathways have been described: the ‘humoral pathway’, which involves cytokine passage through leaky regions in the BBB, such as the circumventricular organs, and the binding of cytokines to saturable transport molecules on the BBB; and the ‘neural pathway’, which involves the binding of cytokines to peripheral afferent nerve fibres, such as the vagus nerve, that in turn stimulate ascending catecholaminergic fibres in the brain and/or are translated back into central cytokine signals16. More recently, however, attention has shifted to a third pathway referred to as the ‘cellular pathway’, which involves the trafficking of activated immune cells, typically monocytes, to the brain vasculature and parenchyma. The details of this pathway have been elegantly dissected in the context of behavioural changes in mice that are associated with peripherally induced inflammation in the liver65. In these studies, the release of TNF from inflamed liver was found to stimulate microglial cell production of CC-chemokine ligand 2 (CCL2; also known as MCP1) that then attracted monocytes to the brain65. Blockade of monocyte infiltration to the brain using antibodies specific for the adhesion molecules P-selectin and α4 integrin abrogated depressive-like behaviour in this animal model65. Of note, cytokine-stimulated astrocytes also may be major producers of chemokines, such as CCL2 and CXC-chemokine ligand 1 (CXCL1), that attract immune cells to the brain66. The cellular pathway additionally has been elucidated in the context of social defeat stress, whereby GFP-labelled monocytes coalesced in several regions of the brain associated with the detection of threat (for example, amygdala) — an effect that was dependent on CCL2 and was facilitated by mobilization of monocytes from the bone marrow as a result of stress-induced release of catecholamines67,68 (FIG. 2). Of note, initial microglial activation during social defeat stress appeared to be a result of neuronal activation by catecholamines and decreased neuronal production of CX3C-chemokine ligand 1 (CX3CL1; also known as fractalkine), which maintains microglia in a quiescent state67,68. Interestingly, this cellular pathway has received intriguing support from post-mortem analyses of brain tissue from patients with depression who committed suicide that showed increased numbers of perivascular macrophages in association with increased gene expression of allograft inflammatory factor 1 (AIF1, also known as IBA1) and CCL2, which are associated with macrophage activation and cellular trafficking59.

This evidence of peripheral myeloid cells trafficking to the brain during depression constitutes some of the first data supporting the existence of a central inflammatory response in human depression that is primarily driven by peripheral inflammatory events. Moreover, data demonstrate that antibodies that are specific for TNF but which do not cross the BBB, can block stress-induced depression in mice69. These findings indicate that peripheral inflammatory responses not only can provide important clues to the immunological mechanisms of inflammation in depression but also may serve as biomarkers and targets of immune-based therapies for depression. Protein biomarkers such as plasma CRP and TNF as well as immunotherapies targeting individual cytokines such as TNF, IL-1 and IL-6 may be most relevant in this regard. Of note, plasma CRP is a strong response predictor in anti-cytokine therapy70.

Cytokines and Neurotransmitters

Given the pivotal importance of neurotransmission to mood regulation, attention has been paid to the impact of inflammation and inflammatory cytokines on the monoamines serotonin, noradrenaline and dopamine, as well as on the excitatory amino acid glutamate (FIG. 3). There are several pathways through which inflammatory cytokines can lead to reduced synaptic availability of the monoamines, which is believed to be a fundamental mechanism in the pathophysiology of depression71. For example, IL-1β and TNF induction of p38 mitogen-activated protein kinase (MAPK) has been shown to increase the expression and function of the reuptake pumps for serotonin, leading to decreased synaptic availability of serotonin and depressive-like behaviour in laboratory animals72. Through the generation of reactive oxygen and nitrogen species, inflammatory cytokines have also been found to decrease the availability of tetrahydrobiopterin (BH4), a key enzyme co-factor in the synthesis of all monoamines that is highly sensitive to oxidative stress73. Indeed, CSF concentrations of BH4 have been shown to be negatively correlated with CSF levels of IL-6 in patients treated with the inflammatory cytokine IFNα74. In addition, the plasma phenylalanine to tyrosine ratio, an indirect measure of BH4 activity, was shown to correlate with CSF concentrations of dopamine as well as symptoms of depression in IFNα-treated patients74. Activation of the enzyme indoleamine 2,3-dioxygenase (IDO) is also believed to be involved in cytokine-induced neurotransmitter alterations, in part by diverting the metabolism of tryptophan (the primary amino acid precursor of serotonin) into kynurenine, a compound that can be converted into the neurotoxic metabolite quinolinic acid by activated microglia and infiltrating monocytes and macrophages in the brain75,76. Of note, increased levels of quinolinic acid have been found in microglia in the ACC of suicide victims who suffered from depression77. Quinolinic acid directly activates receptors for glutamate (that is, N-methyl-D-aspartate (NMDA) receptors) while also stimulating glutamate release and blocking glutamate reuptake by astrocytes78. The effects of quinolinic acid on glutamate converge with the direct effects of pro-inflammatory cytokines on glutamate metabolism that include decreasing the expression of astrocyte glutamate reuptake pumps and stimulating astrocytic glutamate release79, ultimately contributing to excessive glutamate both within and outside the synapse. The binding of glutamate to extrasynaptic NMDA receptors leads to increased excitotoxicity and decreased production of brain-derived neurotrophic factor (BDNF)80. BDNF fosters neurogenesis, an important prerequisite for an antidepressant response, and has been shown to be reduced by IL-1β and TNF and their downstream signalling pathways including NF-κB in stress-induced animal models of depression81,82. Increased levels of glutamate in the basal ganglia and dorsal ACC (dACC) — as measured by magnetic resonance spectroscopy (MRS) — have been described in patients receiving IFNα, and higher levels of glutamate correlated with an increase in depressive symptoms83. More recent data indicate that in patients with depression, increased inflammation as reflected by a CRP >3 mg L−1 is also associated with increased basal ganglia glutamate (compared with patients with a CRP <1 mg L−1) that correlated with anhedonia and decreased psychomotor speed84. Interestingly, blocking glutamate receptors with ketamine or inhibiting IDO activity protects mice from LPS- or stress-induced depressive-like behaviour but leaves the inflammatory response intact85,86. These results indicate that increased activation of glutamate receptors by glutamate and/or quinolinic acid may be a common pathway through which inflammation causes depressive-like behaviour, suggesting that drugs that block glutamate receptor signalling and/or activation of the IDO pathway and its downstream metabolites might have unique applicability to patients with depression and increased inflammation. Importantly, conventional antidepressant medications act by increasing synaptic availability of monoamines and increasing neurogenesis through induction of BDNF87. Therefore, cytokines such as IL-1β and TNF serve to undermine these activities as they decrease the synaptic availability of monoamines while also decreasing BDNF and increasing extracellular glutamate, which is not a target of conventional antidepressant therapy. These cytokine-driven effects may explain the observations that increased inflammation is associated with less robust antidepressant treatment responses and that treatment-resistant patients exhibit increased inflammatory markers88.

Figure 3 Cytokine Targets in the Brain | El Paso, TX Chiropractor

Figure 3: Cytokine targets in the brain: neurotransmitters and neurocircuits. Once in the brain, the inflammatory response can affect metabolic and molecular pathways influencing neurotransmitter systems that can ultimately affect neurocircuits that regulate behaviour, especially behaviours relevant to decreased motivation (anhedonia), avoidance and alarm (anxiety), which characterize several neuropsychiatric disorders including depression. On a molecular level, pro-inflammatory cytokines including type I and II interferons (IFNs), interleukin-1β (IL-1β) and tumour necrosis factor (TNF) can reduce the availability of monoamines — serotonin (5-HT), dopamine (DA) and noradrenaline (NE) — by increasing the expression and function of the presynaptic reuptake pumps (transporters) for 5-HT, DA and NE through activation of mitogen-activated protein kinase (MAPK) pathways and by reducing monoamine synthesis through decreasing enzymatic co-factors such as tetrahydrobiopterin (BH4), which is highly sensitive to cytokine-induced oxidative stress and is involved in the production of nitric oxide (NO) by NO synthase (NOS). Many cytokines, including IFNγ, IL-1β and TNF, can also decrease relevant monoamine precursors by activating the enzyme indoleamine 2,3-dioxygenase (IDO), which breaks down tryptophan, the primary precursor for serotonin, into kynurenine. Activated microglia can convert kynurenine into quinolinic acid (QUIN), which binds to the N-methyl-D-aspartate receptor (NMDAR), a glutamate (Glu) receptor, and together with cytokine-induced reduction in astrocytic Glu reuptake and stimulation of astrocyte Glu release, in part by induction of reactive oxygen species (ROS) and reactive nitrogen species (RNS), can lead to excessive Glu, an excitatory amino acid neurotransmitter. Excessive Glu, especially when binding to extrasynaptic NMDARs, can in turn lead to decreased brain-derived neurotrophic factor (BDNF) and excitotoxicity. Inflammation effects on growth factors such as BDNF in the dentate gyrus of the hippocampus can also affect fundamental aspects of neuronal integrity including neurogenesis, long-term potentiation and dendritic sprouting, ultimately affecting learning and memory. Cytokine effects on neurotransmitter systems, especially DA, can inhibit several aspects of reward motivation and anhedonia in corticostriatal circuits involving the basal ganglia, ventromedial prefrontal cortex (vmPFC) and subgenual and dorsal anterior cingulate cortex (sgACC and dACC, respectively), while also activating circuits regulating anxiety, arousal, alarm and fear including the amygdala, hippocampus, dACC and insula. BH2, dihydrobiopterin; DAT, dopamine transporter; EAAT2, excitatory amino acid transporter 2; NET, noradrenaline transporter; NF-κB, nuclear factor-κB; SERT, serotonin transporter; TH, tyrosine hydroxylase; TPH, tryptophan hydroxylase. Copyrighted 2015. Advanstar. 120580:1115BN.

Effects of Inflammation on Neurocircuitry

Given the impact of cytokines on neurotransmitter systems that regulate the functional activity of neurocircuits throughout the brain, it is no surprise that neuroimaging studies have revealed cytokine-induced alterations in regional brain activity. Consistent with the evolutionary advantages of the partnership between the brain and the immune system, primary cytokine targets in the CNS involve those brain regions that regulate motivation and motor activity (promoting social avoidance and energy conservation) as well as arousal, anxiety and alarm (promoting hypervigilance and protection against attack) (FIG. 3).

Dopamine has a fundamental role in motivation and motor activity, and cytokines have been shown to decrease the release of dopamine in the basal ganglia in association with decreased effort-based motivation as well as reduced activation of reward circuitry in the basal ganglia, in particular the ventral striatum89–91. Inflammatory stimuli have been associated with reductions in reward responsiveness in the striatum across many neuroimaging platforms, demonstrating the validity and reproducibility of these cytokine-mediated effects on the brain in otherwise non-depressed individuals peripherally administered IFNα, endotoxin or typhoid vaccination and imaged by PET, functional magnetic resonance imaging (fMRI), MRS and quantitative magnetization transfer imaging83,89,90,92,93. Interestingly, recent fMRI studies suggest that inflammation-induced decreases in responsiveness to positive reward are also associated with increased sensitivity to aversive stimuli (that is, negative reinforcement) and reduced responsiveness to novelty in the substantia nigra (which is another dopamine-rich structure in the basal ganglia)93,94. Typhoid vaccination has also been shown to activate the subgenual ACC (sgACC), a brain region implicated in depression, and to decrease connectivity of the sgACC with the ventral striatum, an effect modulated by plasma IL-6 (REF. 26). These fMRI findings have recently been extended to patients with depression whose increased plasma CRP level is associated with decreased functional connectivity within reward-related circuits including the ventral striatum and the ventromedial prefrontal cortex that, in turn, mediates the relationship between CRP and anhedonia95. Indeed, patients with depression with a CRP >3 mg L−1 had little, if any, connectivity within reward-related circuits as measured by fMRI, whereas connectivity in patients with depression with a CRP <1 mg L−1 was similar to healthy controls95. Taken together, these data support the notion that the effect of cytokines on the brain in general and dopaminergic pathways in particular lead to a state of decreased motivation or anhedonia, which is a core symptom of depression.

fMRI studies have demonstrated that increased inflammation is also associated with increased activation of threat- and anxiety-related neurocircuitry, including the dACC as well as the insula and amygdala26,96,97. Of note, the dACC and amygdala are regions that exhibit increased activity in patients with high-trait anxiety and neuroticism98, conditions that often accompany depression and are associated with increased inflammation. For example, increased concentrations of oral IL-6 and soluble TNF receptor 2 (also known as TNFRSF1B) in response to a public speaking stressor was significantly correlated with the response of the dACC to a social rejection task97. In addition, increased oral IL-6 expression in response to a social evaluation stressor was significantly correlated with activation of the amygdala, with subjects who exhibited the highest IL-6 responses to stress demonstrating the greatest connectivity within threat circuitry, including the amygdala and the dorsomedial prefrontal cortex, as measured by fMRI99. Interestingly, these data are consistent with the trafficking of monocytes to the amygdala during social defeat stress in mice68.

Risk and Resilience

Increased Inflammation and the Risk for Depression

Consistent with the emerging recognition that inflammation may cause depression in certain subgroups of individuals, epidemiological studies on large community samples — as well as smaller samples of medically ill individuals — have demonstrated that increased inflammation serves as a risk factor for the future development of depression. For example, increased peripheral blood CRP and IL-6 concentrations were found to significantly predict depressive symptoms after 12 years of follow up in the Whitehall II study of over 3,000 individuals, whereas no association was found between the presence of depressive symptoms and subsequent blood CRP and IL-6 levels100. Similar findings were reported in the English Longitudinal Study of Ageing in which a CRP >3 mg L−1 predicted depressive symptoms and not vice versa101. Of note, however, some studies have found no longitudinal relationship between depression and inflammation, and others have found that depression leads to increased inflammation102. Other factors known to be associated with increased peripheral inflammation, including childhood and adult trauma, have also been shown to be predictive of a greater risk of developing depression103,104.

Both genetic and epigenetic mechanisms may explain why childhood or adult traumas can contribute to exaggerated or persistent inflammation and, ultimately, depression. For example, polymorphisms in CRP were associated not only with increased peripheral blood concentrations of CRP but also with symptoms of post-traumatic stress disorder, especially heightened arousal, in individuals exposed to civilian trauma32. Moreover, gene–environment interactions have been found to influence depression severity in response to chronic interpersonal stress: individuals carrying polymorphisms in IL1B that are associated with higher expression of peripheral IL-1β exhibited more severe depressive symptoms in the context of interpersonal stress than individuals without the IL1B risk allele105. Similarly, mice in which peripheral blood leukocytes produced high concentrations of LPS-induced IL-6 ex vivo before stress exposure showed decreased social exploration after social defeat stress, whereas mice that produced low levels of IL-6 before stress exposure exhibited no behavioural effects in response to social defeat88. Of note, adoptive transfer of bone marrow progenitor cells from mice producing high levels of IL-6 ex vivo to mice that produced low levels of IL-6 made these formerly stress-resilient animals sensitive to the depressive effects of social defeat88.

Epigenetic changes in genes related to inflammation may also affect the risk for depression and anxiety in the context of psychosocial stress. Indeed, the well-documented association of childhood trauma with increased inflammation is linked to stress-induced epigenetic changes in FKBP5, a gene implicated in the development of depression and anxiety as well as in the sensitivity to glucocorticoids106. Allele-specific, childhood trauma-dependent DNA demethylation in functional glucocorticoid response elements of FKBP5 were found to be associated with decreased sensitivity of peripheral blood immune cells to the inhibitory effects of the synthetic glucocorticoid dexamethasone on LPS-induced production of IL-6 in vitro106. Of note, decreased activation of glucocorticoid receptor-responsive genes in association with increased activation of genes regulated by NF-κB has been found to be a ‘fingerprint’ of the effects of chronic stress in several studies examining a variety of psychosocial stressors39,107.

T Cells and Resilience to Depression

Some of the most intriguing data regarding the role of the immune system in depression come from studies showing that T cells may protect against stress and depression in laboratory animals. For example, the adoptive transfer of T cells from animals exposed to chronic social defeat stress led to an antidepressant behavioural phenotype in stress-naive mice, which was associated with decreased pro-inflammatory cytokines in serum, a shift towards a neuroprotective M2 phenotype in microglia and increased neurogenesis in the hippocampus108. Similar results have been reported following acute stress in mice, in which effector T cell migration to the choroid plexus as a result of glucocorticoid induction of intercellular adhesion molecule 1 (ICAM1) expression in the choroid plexus was associated with reduced anxiety-like behaviour109. Mice with impaired release of glucocorticoids in response to stress were anxiety prone109. Immunization of anxiety-prone animals with a CNS-specific antigen restored T cell trafficking to the brain during stress and reversed anxiety-like behaviour in association with increased neurogenesis109. Immunization with a CNS-specific antigen also blocked stress-induced depression in mice110. The mechanism by which T cells influence resilience is believed to be related to their production of IL-4 within the meningeal space. Through as yet uncharacterized pathways, IL-4 then stimulates astrocytes to produce BDNF, and also promotes the conversion of meningeal monocytes and macrophages from a pro-inflammatory M1 phenotype to a less inflammatory M2 phenotype111. The movement of T cells throughout the brain, including the meningeal space, has become an area of special interest with the recent description of a brain lymphatic system that heretofore had gone unrecognized112. Data also indicate that TReg cells may have a role in reducing inflammation and supporting neuronal integrity during stress113. Similar reports have characterized T cells that are activated by vagal nerve stimulation to produce acetylcholine, which can inhibit NF-κB activation by binding to the α7 subunit of the nicotinic acetylcholine receptor114.

Relevant to depression, however, peripheral T cell trafficking in response to glucocorticoids has been shown to be impaired in patients with depression, possibly owing to glucocorticoid resistance as a result of genetically mediated (for example, FKBP5) or inflammasome-mediated mechanisms targeting the glucocorticoid receptor46,115. In addition, inflammatory cytokines and their signalling pathways, including p38 MAPK, have direct inhibitory effects on glucocorticoid receptor function116. Moreover, patients with depression have been shown to have increased numbers of peripheral blood myeloid-derived suppressor cells, which inhibit T cell function117. Of note, activation of the NLRP3 inflammasome leads to increased accumulation of myeloid-derived suppressor cells118. Decreased numbers of peripheral blood TReg cells and reduced concentrations of anti-inflammatory cytokines in the blood, including TGFβ and IL-10, have also been reported in depression119. Thus, it appears that patients with depression may have impairments in neuroprotective and anti-inflammatory T cell responses.

These findings suggest that therapies that boost such T cell responses could be used in patients with depression. Examples include immunization strategies (with CNS antigens as discussed above) that attract T cells to the brain or administration of bacteria, such as Mycobacterium vaccae, or parasites that stimulate TReg cell responses or T cell production of IL-4 (REFS 14,109,110,120). Indeed, colonization of pregnant dams with helminths attenuated the increase of hippocampal IL-1β in neonatal rats infected with bacteria and protected these animals from the subsequent development of microglial sensitization and cognitive dysfunction in adulthood. This effect was associated with increased ex vivo production of IL-4 and decreased production of IL-1β and TNF by splenic macrophages in response to LPS stimulation120. Finally, vagus nerve stimulation could be used to induce anti-inflammatory acetylcholine-producing T cells121. Although many strategies exist to activate anti-inflammatory T cell responses including the induction of TReg cells by administration of mesenchymal stem cells122, the majority of the approaches discussed above have proof-of-concept data in animal models of depression. Nevertheless, the clinical relevance of these approaches has yet to be determined by randomized clinical trials in patients with depression.

Translational Considerations

Our increasing understanding of how inflammatory processes contribute to depression, combined with the growing frustration over the lack of discovery of new antidepressants, have stimulated interest in the possibility that various classes of anti-inflammatory medications or other anti-inflammatory strategies (as discussed above) may hold promise as novel ‘all-purpose’ antidepressants. Unfortunately, it appears that anti-inflammatory agents may only demonstrate effective antidepressant activity in subgroups of patients who show evidence of increased peripheral inflammation, for example individuals with medical conditions including osteoarthritis and psoriasis that are characterized by increased levels of peripheral inflammation and patients with depression with increased inflammatory markers29,30. Moreover, in patients with depression who do not show elevated peripheral levels of inflammation, anti-inflammatory treatments may actually impair placebo responses that contribute to the effectiveness of all known antidepressant modalities123. In the only study to date examining the antidepressant effect of a cytokine antagonist in medically healthy adults with treatment-resistant depression, post hoc analysis revealed a dose-response relationship between baseline levels of peripheral inflammation and subsequent antidepressant response to the TNF inhibitor infliximab30. In patients with baseline plasma CRP concentrations ≥5 mg L−1, infliximab outperformed placebo with an effect size similar to that observed in studies of standard antidepressants. Patients with a CRP >3 mg L−1, the standard cut-off for high inflammation, also exhibited separation from placebo. Of note, this latter finding along with data demonstrating the relevance of a CRP >3 mg L−1 to altered reward circuitry and glutamate metabolism in depression as well as the prediction of subsequent depressive episodes (described above) aligns well with other diseases in which a CRP >3 mg L−1 is relevant to prediction and pathology including cardiovascular disease and diabetes. These data suggest that the cut-off for high inflammation in depression may be consistent with other disorders (BOX 2). Importantly, however, in patients with lower levels of inflammation, blockade of TNF with infliximab actually impaired the placebo response30, suggesting that anti-inflammatory treatments in patients without inflammation may be detrimental, highlighting the growing recognition that the immune system has an important role in several processes central to neuronal integrity.

Guidelines for Anti-Inflammatory Clinical Trials in Depression

Based on the animal and human literature on the effects of cytokines on the brain, the following guidelines can inform clinical trials designed to test the cytokine hypothesis of depression.

  • Inflammation only occurs in subgroups of patients with depression30. Clinical trials should enrich for patient populations with evidence of increased inflammation, particularly those identified by a C-reactive protein (CRP) >3 mg L−1, which has been shown to characterize patients with depression with altered reward circuitry and increased basal ganglia glutamate, as well as those who have shown a response to anti-cytokine therapy30,84,95.
  • Anti-inflammatory drugs may harm patients without increased inflammation. Inflammatory cytokines and the innate immune response have pivotal roles in synaptic plasticity, neurogenesis, long-term potentiation (which is a fundamental process in learning and memory) and possibly antidepressant response123,128.
  • Primary behavioural outcome variables should include measures of anhedonia and anxiety. Neuroimaging studies coupled with studies administering a variety of inflammatory stimuli, including the inflammatory cytokine interferon-α, endotoxin and typhoid vaccination, have revealed that inflammation targets neurocircuits in the brain that regulate motivation and reward as well as anxiety, arousal and alarm35. In addition, these symptoms have been shown to respond to anti-cytokine therapy in limited studies.
  • Drugs that specifically target inflammatory cytokines and/or their signalling pathways are preferable. The majority of clinical trials to date have used anti-inflammatory drugs (non-steroidal anti-inflammatory agents and minocycline, a tetracycline antibiotic) that have several off-target effects making the extant data relevant to testing the cytokine hypothesis of depression difficult to interpret31.
  • Target engagement must be established in the periphery and ultimately the brain. Protein and gene expression markers of inflammation in the peripheral blood can serve as relevant proxies for inflammation in the brain129, especially given evidence of trafficking of activated peripheral immune cells to the brain in stress-induced animal models of depression. Relevant therapeutic interventions should decrease peripheral inflammatory markers in concert with improvement of specific depressive symptoms. Translocator protein neuroimaging ligands may ultimately serve as direct measures of neuroinflammation and its inhibition by anti-inflammatory therapies in future clinical trials61.

We conclude by offering the balanced perspective that anti-inflammatory therapies are unlikely to be all-purpose antidepressants. Perhaps we only think of standard antidepressants as all-purpose agents because we have never succeeded in developing predictive biomarkers that would reliably inform us of who will respond to any given agent. If so, then we view these agents as all-purpose, not because it is true but out of hope and ignorance. Thus, instead of being a negative, perhaps the finding that baseline inflammatory biomarkers such as CRP can predict subsequent symptomatic response to anti-inflammatory strategies is, in fact, the most positive development thus far in our quest to understand how the immune system might be harnessed to improve the treatment of depression.

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Dr. Alex Jimenez’s Insight

When you catch a cold, certain symptoms are triggered by inflammatory markers released in response to illness. While sneezing, coughing and a sore throat serve as the most “obvious” signs you may be sick, what truly keeps you in bed when you have a cold is the accompanying fatigue, inattentiveness, loss of appetite, change in sleep pattern, heightened perception of pain and apathetic withdrawal. These symptoms are similar to the wide array of symptoms that define depression. Many research studies have demonstrated that depression may occur due to an inflammatory response to illness, just as in the case of a common cold. The connection between inflammation and depression has long been argued among healthcare professionals and researchers, where new evidence could open the doors to additional treatment approaches which could help better manage this debilitation health issue.

Conclusion

In ancestral times, integration of inflammatory responses and behaviours of avoidance and alarm provided an evolutionary advantage in managing the microbial world. In the absence of the temporizing influence of commensal organisms that were rife in environments in which humans evolved, the inflammatory bias of the human species in the civilized world has been increasingly engaged in the complex world of psychosocial interactions and the inevitable stress it engenders. Responding to these sterile insults with activation of the inflammasome and mobilization of myeloid cells to the brain, the resultant release of inflammatory cytokines impinges on neurotransmitters and neurocircuits to lead to behaviours that are poorly suited for functioning in modern society. This inevitability of our evolutionary past is apparent in the high rates of depression that are seen in society today. There is also an increasing recognition of mechanisms of resilience that derive from our emerging understanding of the neuroprotective effects of a variety of T cell responses ranging from effector T cells that produce IL-4 to TReg cells with anti-inflammatory properties. A better understanding of these neuroprotective pathways and of the inflammatory mechanisms — from inflammasome activation to cell trafficking to the brain — that operate in patients with depression may lead to the development of novel anti-depressant therapies.

For glossary and footnotes visit: Ncbi.nlm.nih.gov/pmc/articles/PMC5542678/

Understanding the Phytocannabinoids

The discovery of the body’s endocannabinoid system, or ECS, in the 1980s provided researchers a totally new outlook on the chemicals in marijuana and hemp that had formerly been identified 40 years earlier, including how these chemicals interacted with and acted on a prevalent regulatory system in the human body. The title given to those chemicals was phytocannabinoids, meaning “phyto” for plantlife. Over 80 phytocannabinoids are identified in marijuana and hemp. The psychoactive phytocannabinoid in marijuana, tetrahydrocannabinol, or THC, represents only one of many phytocannabinoids now being extensively studied for its numerous health benefits. The more science learns about the far-reaching effects of the ECS in encouraging brain health, in improving immune function, in keeping a healthy inflammatory response, and in promoting GI health, fertility, bone health, and much more, the more interest there is in locating these phytocannabinoids in nature and learning how they affect human health. Due to this widespread interest, phytocannabinoids have been identified in many plants outside the Cannabis species; for instance, plants such as clove, black pepper, Echinacea, ginseng, broccoli, and carrots, all contain phytocannabinoids.

Phytocannabinoids in Hemp

Although the majority of people have now heard of cannabadiol (CBD), it’s only one of lots of the constituents in hemp which interact with the ECS. Two other notable phytocannabinoids include:

Cannabichromene (CBC)

CBC was first analyzed in the 1980s as it was found to modulate a normal inflammatory response in a rat model. More recently CBC has been shown to promote brain health, skin health, and preserve normal motility in the digestive tract.

Cannabigerol (CBG)

CBG has been increasingly studied for its capacity to support nervous system health. CBG has multiple roles from the ECS, such as inhibiting the reuptake of anandamide, an extremely beneficial endocannabinoid we make within our own bodies. CBG might also provide help for immune function, skin health, and a positive disposition. CBG is typically found in much higher concentrations in industrial hemp than in marijuana.

Phytocannabinoids in Other Crops

There is also ongoing research in discovering phytocannabionids in many other plants. Some of them include:

Beta-Caryophyllene (BCP)

Although BCP is located from the flowers and leaves of hemp, since just the hemp stalk is used in nutritional supplements, even BCP content is lost. But, BCP is contained in many other plants, like cloves and black pepper. BCP binds to the CB2 cannabinoid receptor in the body, and by doing so it helps maintain a healthy inflammatory reaction and promotes the overall health of the digestive tract, skin, and liver disease.

Diindolylmethane (DIM)

DIM is a compound we create in our bodies when we eat cruciferous vegetables like broccoli, cauliflower, cabbage, and Brussels sprouts. DIM is also a readily available nutritional supplement. Much like beta-caryophyllene, DIM binds to the CB2 cannabinoid receptor. Since the immune system is rich with CB2 receptors, this may clarify the immune-supportive health benefits of the foods.

Alkylamides

Located in the familiar herb Echinacea, alkylamides are also drawing interest for their part in the ECS. These unique compounds act on the CB2 cannabinoid receptor to regulate cytokine synthesis and also to support immune function. This activity probably helps clarify some of the common uses of Echinacea.

Falcarinol

Found in carrots, celery, parsley, and Panax ginseng, this interesting compound may not be one need to touch. Falcarinol binds to the CB1 cannabinoid receptor which also has the reverse effect of anandamide, that the cannabinoid our bodies make that binds to the receptor. Because of this trend, falcarinol can cause an allergic skin reaction that’s regarded because it prevents our very own ECS from modulating local inflammation.

Yangonin

This phytocannabinoid, found from the Kava plant (Piper methysticum), binds to CB1 cannabinoid receptors and also acts on GABA receptors in the nervous system. Although yangonin appears to promote relaxation and modulate responses to stress, it might also be bad for the liver.

Understanding of the endocannabinoid system is growing quickly. As this knowledge does enlarge, science will continue to find more phytocannabinoids in plants and foods that are useful in supporting health in many ways.

In conclusion, many research studies have found a connection between inflammatory pathways and neurocircuits in the brain which can lead to a variety of behavioral responses, such as avoidance and alarm, however, growing evidence has demonstrated that chronic inflammation can lead to depression. Depression is a debilitating disorder which amounts to one of the leading causes of disability worldwide. The article above describes the connection between inflammation and depression. New insights on the results of the research studies could open the possibilities for new treatments to treat depression, among other associated health issues. Moreover, understanding the role of phytocannabinoids in the human body can function as another treatment approach for inflammation associated with depression.  Information referenced from the National Center for Biotechnology Information (NCBI). The scope of our information is limited to chiropractic as well as to spinal injuries and conditions. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at 915-850-0900 .

Curated by Dr. Alex Jimenez

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Additional Topics: Back Pain

Back pain is one of the most prevalent causes for disability and missed days at work worldwide. As a matter of fact, back pain has been attributed as the second most common reason for doctor office visits, outnumbered only by upper-respiratory infections. Approximately 80 percent of the population will experience some type of back pain at least once throughout their life. The spine is a complex structure made up of bones, joints, ligaments and muscles, among other soft tissues. Because of this, injuries and/or aggravated conditions, such as herniated discs, can eventually lead to symptoms of back pain. Sports injuries or automobile accident injuries are often the most frequent cause of back pain, however, sometimes the simplest of movements can have painful results. Fortunately, alternative treatment options, such as chiropractic care, can help ease back pain through the use of spinal adjustments and manual manipulations, ultimately improving pain relief.

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EXTRA IMPORTANT TOPIC: Low Back Pain Management

MORE TOPICS: EXTRA EXTRA: Chronic Pain & Treatments

 

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How the Nervous System Processes Chronic Pain

How the Nervous System Processes Chronic Pain

How does your brain know when you are experiencing pain? How does it know the difference between the soft touch of a feather and a needle prick? And, how does that information get to your body in time to respond? How can acute pain become chronic pain? These aren’t simple answers, but with a small explanation about how the nervous system works, you need to have the ability to comprehend the basics before considering any type of treatment approach for chronic pain.

 

Your nervous system is made up of 2 main parts: the brain and the spinal cord, which unite to form the central nervous system; and both sensory and motor nerves, that form the peripheral nervous system. The names make it easy to picture: the brain and spinal cord are the hubs, whereas the sensory and motor nerves stretch out to provide access to all areas of the body. Put simply, sensory nerves send impulses about what is going on in our environment to the brain through the spinal cord. The brain sends data back into the motor nerves, which help us execute tasks. It is like using an extremely complicated inbox and outbox for everything. The purpose of the article below is to demonstrate the process by which the human nervous system processes chronic pain.

 

Pain Processing in the Human Nervous System: A Selective Review of Nociceptive and Biobehavioral Pathways

 

Abstract

 

This selective review discusses the psychobiological mediation of nociception and pain. Summarizing literature from physiology and neuroscience, first an overview of the neuroanatomic and neurochemical systems underpinning pain perception and modulation is provided. Second, findings from psychological science are used to elucidate cognitive, emotional, and behavioral factors central to the pain experience. This review has implications for clinical practice with patients suffering from chronic pain, and provides strong rationale for assessing and treating pain from a biopsychosocial perspective.

 

Keywords: pain, nociception, neurobiology, autonomic, cognitive, affective

 

Introduction

 

Pain is a complex, biopsychosocial phenomenon that arises from the interaction of multiple neuroanatomic and neurochemical systems with a number of cognitive and affective processes. The International Association for the Study of Pain has offered the following definition of pain: “Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.”[1] (p210) Thus, pain has sensory and affective components, as well as a cognitive component reflected in the anticipation of future harm. The purpose of the following review is to integrate the literature on the neurobiological pathways within the central, autonomic, and peripheral nervous systems that mediate pain processing, and discuss how psychological factors interact with physiology to modulate the experience of pain.

 

Functional Neuroanatomy and Neurochemistry of Pain

 

Pain Processing in the Nervous System

 

When noxious stimuli impinge upon the body from external or internal sources, information regarding the damaging impact of these stimuli on bodily tissues is transduced through neural pathways and transmitted through the peripheral nervous system to the central and autonomic nervous systems. This form of information processing is known as nociception. Nociception is the process by which information about actual tissue damage (or the potential for such damage, should the noxious stimulus continue to be applied) is relayed to the brain. Nociception is mediated by specialized receptors known as nociceptors that are attached to thin myelinated Aδ and unmyelinated C fibers, which terminate in the dorsal horn of the spine. Sufficiently intense mechanical stimulation (such as stretching, cutting, or pinching), intense warming of the skin, or exposure to noxious chemicals can activate nociceptors.[2] In turn, activation of nociceptors is modulated by inflammatory and bio-molecular influences in the local extracellular environment.[3] Although under most circumstances transmission of nociceptive information results in pain perception, many physicians and patients are unaware that nociception is dissociable from the experience of pain. In other words, nociception can occur in the absence of awareness of pain, and pain can occur in the absence of measurably noxious stimuli. This phenomenon is observable in instances of massive trauma (such as that which might be incurred by a motor vehicle accident) when victims exhibit a stoic painless state despite severe injury, and conversely, when individuals with functional pain syndromes report considerable anguish in spite of having no observable tissue damage.

 

In contrast, perception of pain occurs when stimulation of nociceptors is intense enough to activate Aδ fibers, resulting in a subjective experience of a sharp, prickling pain.[4] As stimulus strength increases, C fibers are recruited, and the individual experiences an intense, burning pain that continues after the cessation of the stimulus. These types of experiences occur during the two phases of pain perception that occur following an acute injury.[2] The first phase, which is not particularly intense, comes immediately after the painful stimulus and is known as fast pain. The second phase, known as slow pain, is more unpleasant, less discretely localized, and occurs after a longer delay.

 

Activation of nociceptors is transduced along the axons of peripheral nerves which terminate in the dorsal horn of the spine. There, messages are relayed up the spinal cord and through the spinothalamic tract to output on the thalamus. In turn, the thalamus serves as the major “relay station” for sensory information to the cerebral cortex.[5] Nociceptive pathways terminate in discrete subdivisions of thalamic nuclei known as the ventral posterior lateral nucleus and the ventromedial nucleus.[6] From these nuclei, nociceptive information is relayed to various cortical and subcortical regions, including the amygdala, hypothalamus, periaqueductal grey, basal ganglia, and regions of cerebral cortex. Most notably, the insula and anterior cingulate cortex are consistently activated when nociceptors are stimulated by noxious stimuli, and activation in these brain regions is associated with the subjective experience of pain.[7] In turn, these integrated thalamocortical and corticolimbic structures, which collectively have been termed the pain “neuromatrix,” process somatosensory input and output neural impulses which influence nociception and pain perception.[8]

 

Neurochemistry of Pain

 

Nociception is mediated by the function of numerous intra- and extra-cellular molecular messengers involved in signal transduction in the peripheral and central nervous systems. All nociceptors, when activated by the requisite mechanical, thermal, or chemical stimulus, transmit information via the excitatory neurotransmitter glutamate.[9] In addition, inflammatory mediators are secreted at site of the original injury to stimulate nociceptor activation. This “inflammatory soup” is comprised of chemicals such as peptides (e.g., bradykinin), neurotransmitters (e.g., serotonin), lipids (e.g., prostaglandins), and neurotrophins (e.g., NGF). The presence of these molecules excites nociceptors or lowers their activation threshold, resulting in the transmission of afferent signals to the dorsal horn of the spinal cord as well as initiating neurogenic inflammation.[3] Neurogenic inflammation is the process by which active nociceptors release neurotransmitters such as substance P from the peripheral terminal to induce vasodilation, leak proteins and fluids into the extracellular space near the terminal end of the nociceptor, and stimulate immune cells which contribute to the inflammatory soup. As a result of these neurochemical changes in the local environment of nociceptors, the activation of Aδ and C fibers increases, and peripheral sensitization occurs.[10]

 

In turn, nociceptive signal transduction up the spinothalamic tract results in elevated release of norepinephrine from the locus coeruleus neurons projecting to thalamus, which in turn relays nociceptive information to somatosensory cortex, hypothalamus, and hippocampus.[11,12] As such, norepinephrine modulates the “gain” of nociceptive information as it is relayed for processing in other cortical and subcortical brain regions. Concomitantly, opioid receptors in the peripheral and central nervous systems (e.g., those in neurons of the dorsal horn of the spine and the periaqueductal grey in the brain) result in inhibition of pain processing and analgesia when stimulated by opiates or endogenous opioids like endorphin, enkephalin, or dynorphin.[13] The secretion of endogenous opioids is largely governed by the descending modulatory pain system.[14] The neurotransmitter GABA is also involved in the central modulation of pain processing, by augmenting descending inhibition of spinal nociceptive neurons.[15] A host of other neurochemicals are also involved in pain perception; the neurochemistry of nociception and central-peripheral pain modulation is extremely complex.

 

Descending Central Modulation of Pain

 

The brain does not passively receive pain information from the body, but instead actively regulates sensory transmission by exerting influences on the spinal dorsal horn via descending projections from the medulla.[16] In their seminal Gate Control theory of pain, Melzack and Wall proposed that the substantia gelatinosa of the dorsal horn gates the perception of noxious stimuli by integrating upstream afferent signals from the peripheral nervous system with downstream modulation from the brain.[17] Interneurons in the dorsal horn can inhibit and potentiate impulses ascending to higher brain centers, and thus they provide a site where the central nervous system controls impulse transmission into consciousness.

 

The descending pain modulatory system exerts influences on nociceptive input from the spinal cord. This network of cortical, subcortical, and brainstem structures includes prefrontal cortex, anterior cingulate cortex, insula, amygdala, hypothalamus, periaqueductal grey, rostral ventromedial medulla, and dorsolateral pons/tegmentum.7 The coordinated activity of these brain structures modulates nociceptive signals via descending projections to the spinal dorsal horn. By virtue of the somatotopic organization of these descending connections, the central nervous system can selectively control signal transmission from specific parts of the body.

 

The descending pain modulatory system has both anti- and pro-nociceptive effects. Classically, the descending pain modulatory system has been construed as the means by which the central nervous system inhibits nociceptive signals at the spinal outputs.[16] In a crucial early demonstration, Reynolds observed that direct electrical stimulation of the periaqueductal grey could produce dramatic analgesic effects as evidenced by the ability to undergo major surgery without pain.[18] Yet, this brain system can also facilitate nociception. For instance, projections from the periaqueductal grey to the rostral ventromedial medulla have been shown to enhance spinal transmission of nociceptive information from peripheral nociceptors.[19]

 

Central modulation of pain may have been a conserved across human evolution due to its potentially adaptive effects on survival. For instance, in situations of serious mortal threat (for example, in the face of war and civil accidents, or more primordially, when being attacked by a vicious animal), suppression of pain might enable a severely-injured individual to continue intense physical activity such as fleeing from danger or fighting a deadly opponent. Yet, the neurobiological linkages between the brain, the spinothalamic tract, the dorsal horn, and the peripheral nerves also provide a physiological pathway by which negative emotions and stress can amplify and prolong pain, causing functional interference and considerable suffering.

 

Cognitive, Affective, Psychophysiological, and Behavioral Processes in Pain Perception and Regulation

 

In addition to the somatosensory elements of pain-processing described above, cognitive and emotional factors are implicit within the definition of pain offered by the International Association for the Study of Pain. Pain perception involves a number of psychological processes, including attentional orienting to the painful sensation and its source, cognitive appraisal of the meaning of the sensation, and the subsequent emotional, psychophysiological, and behavioral reaction, which then feedback to influence pain perception (see Figure 1). Each of these processes will be detailed below.

 

Schematic of the Human Nervous System Diagram 1 | El Paso, TX Chiropractor

Figure 1: A schematic of nociception, pain perception and the biobehavioral response to pain in the human nervous system.

 

Attention to Chronic Pain

 

In the brain, attention allows salient subsets of data to gain preeminence in the competitive processing of neural networks at the expense of other subsets of data.[20] The goal-relevance of a stimulus guides attention to select and distinguish it from the environmental matrix in which it is embedded.[21] Thus, attended stimuli receive preferential information processing and are likely to govern behavior. In this sense, attention allows for the evaluation of salient stimuli, and facilitates execution of approach behaviors in response to appetitive stimuli or avoidance behaviors in response to aversive ones. Thus, depending on its salience to the survival of the organism, the object of attention elicits the motivation to approach or avoid, while the resultant emotional state, as the manifestation of approach or avoidance motivations, tunes and directs attention.[22,23] By virtue of its significance for health and well-being, pain automatically and involuntarily attracts attention.[24,25] Yet pain experience varies according to the locus of attention; when attention is focused on pain, it is perceived as more intense,[26] and whereas when attention is distracted from pain, it is perceived as less intense.[27]

 

Attentional modulation of pain experience correlates with changes in activation of the pain neuromatrix; for instance, attentional distraction reduces pain-related activations in somatosensory cortices, thalamus, and insula, among other brain regions.[7] Concomitantly, distraction results in strong brain activations in prefrontal cortex, anterior cingulate cortex, and periaqueductal grey, suggesting an overlap and interaction between brain systems involved in attentional modulation of pain and the descending pain modulatory system.[28] In contrast, attentional hypervigilance for pain, a high degree of monitoring internal and external stimuli that is often observed among persons with chronic pain,[29] amplifies pain intensity and is associated with the interpretation of harmless sensations (like moderate levels of pressure) as painfully unpleasant.[30,31]

 

Cognitive Appraisal of Pain

 

Pain involves a process of cognitive appraisal, whereby the individual consciously or unconsciously evaluates the meaning of sensory signals emanating from the body to determine the extent to which they signify the presence of an actual or potential harm. This evaluation is decidedly subjective. For instance, experienced weightlifters or runners typically construe the “burn” they feels in their muscles as pleasurable and indicative of increasing strength and endurance; in contrast, a novice might view the same sensation as signaling that damage had occurred. The inherent variability of cognitive appraisal of pain may stem from the neurobiological dissociation between the sensory and affective aspects of the pain experience; change in pain intensity results in altered activation of somatosensory cortex, whereas change in pain unpleasantness results in altered activation of the anterior cingulate cortex.[32,33] Thus, a sensory signal originating from the muscles of lower back might be perceived as a warmth and tightness, or viewed as a terrible agony, in spite of the stimulus intensity being held constant. The manner in which the bodily sensation is appraised may in turn influence whether it is experienced as unpleasant pain or not.[34]

 

The extent to which a given bodily sensation is interpreted as threatening is in part dependent on whether or not the individual believes he or she is able to cope with that sensation. If, during this complex cognitive process of appraisal, available coping resources are deemed sufficient to deal with the sensation, then pain can be perceived as controllable. Pain intensity is reduced when pain is perceived to be controllable, whether or not the individual acts to control the pain. Ventrolateral prefrontal cortex activation is positively associated with the extent to which pain is viewed as controllable and negatively correlated with subjective pain intensity. This brain region is implicated in emotion regulation efforts, such as when threatening stimuli are reappraised to be benign.[35,36] Concomitantly, reinterpreting pain as a harmless sensation (e.g., warmth or tightness) predicts higher perceived control over pain,[37] and psychological interventions have been shown to reduce pain severity by increasing reinterpretation of pain sensations as innocuous sensory information.[38] In contrast, pain catastrophizing (i.e., viewing pain as overwhelming and uncontrollable) is associated with greater pain intensity irrespective of the extent of physical impairment[39] and prospectively predicts the development of low back pain.[40]

 

Emotional and Psychophysiological Reactions to Chronic Pain

 

The aversive nature of pain elicits a powerful emotional reaction that feeds back to modulate pain perception. Pain often results in feelings of anger, sadness, and fear depending on the how the pain is cognitively appraised. For instance, the belief “It’s not fair that I have to live with this pain” is likely to lead to anger, whereas the belief “My life is hopeless now that I have this pain” will likely result in sadness. Fear is a common reaction to pain when individuals interpret the sensations from the body as indicating the presence of serious threat.

 

These emotions are coupled with autonomic, endocrine, and immune responses which may amplify pain through a number of psychophysiological pathways. For example, pain induction significantly elevates sympathetic nervous system activity, marked by increased anxiety, heart rate, and galvanic skin response.[41] Furthermore, negative emotions and stress increase contraction of muscle tissue; elevated electromyographic activity occurs in the muscles of the back and neck under conditions of stress and negative affect and is perceived as painful spasms.[42,43] This sympathoexcitatory reaction coupled with emotions like anger and fear may reflect an evolutionarily conserved, active coping response to escape the painful stimulus. Yet negative emotional states intensify pain intensity, pain unpleasantness, and pain-induced cardiovascular autonomic responses, while reducing the sense of perceived control over pain.[44] Stress and negative emotions like anger and fear may temporarily dampen pain via norepinephrine release, but when the sympathetic “fight or flight” response is prolonged it can increase blood flow to the muscle and increase muscle tension which may aggravate the original injury.[45] Alternatively, pain inputs from the viscera and muscles may stimulate cardiac vagal premotor neurons, leading to hypotension, bradycardia, and hyporeactivity to the environment – a pattern of autonomic response that corresponds with passive pain coping and depressed affect.[46] In addition to autonomic reactivity, pro-inflammatory cytokines and the stress hormone cortisol are released during the experience of negative emotion; these bio-molecular factors enhance nociception, facilitate processing of aversive information in the brain, and when their release is chronic or recurrent, may cause or exacerbate tissue damage.[8,47,48]

 

Moreover, negative emotions are associated with increased activation in the amygdala, anterior cingulate cortex, and anterior insula – these brain structures not only mediate the processing of emotions, but are also important nodes of the pain neuromatrix that tune attention toward pain, intensify pain unpleasantness, and amplify interoception (the sense of the physical condition of the body).[49,50] Thus, when individuals experience negative emotions like anger or fear as a result of pain or other emotionally salient stimuli, the heightened neural processing of threat in affective brain circuits primes the subsequent perception of pain[51,52] and increases the likelihood that sensations from within the body will be interpreted as painful.[53–55] The fear of pain, a clinical feature of chronic pain patients, is associated with hypervigilance for and sustained attention to pain-related stimuli.[56] Thus, negative emotions bias attention toward pain, which then increase its unpleasantness. In addition, negative emotions and stress impair prefrontal cortex function, which may reduce the ability to regulate pain using higher order cognitive strategies like reappraisal or viewing the pain as controllable and surmountable.[57,58] Thus, anger, sadness, and fear may result from acute or chronic pain and in turn feedback into the bio-behavioral processes that influence pain perception to exacerbate anguish and suffering.

 

Behavioral Reactions to Pain

 

Pain is not only a sensory, cognitive, and emotional experience, but also involves behavioral reactions that may alleviate, exacerbate, or prolong pain experience. Typical pain behaviors in low back pain include grimacing, rubbing, bracing, guarded movement, and sighing.[59] These behaviors facilitate the communication of pain and exert social influences that may have vicarious gain for the individual suffering from pain; such benefits include sympathy, acts of kindness and generosity, tolerance, lowered expectations, and social bonding, among others.[60] In addition, guarding or avoidance of activities associated with pain may be negatively reinforcing by virtue of the temporary alleviation of pain experience.[61] The fact that these avoidant behaviors decrease the occurrence of pain results in increasing use of avoidance as a coping strategy. Yet, greater use of avoidance as a result of fear of pain predicts higher levels of functional disability.[62] It is not merely that persons with greater pain-related disability engage in more avoidant behaviors, but rather studies indicate that avoidant behavior and beliefs are a precursor to disability.[63–65] Avoidance contributes to negative clinical outcomes in patients with chronic low back pain. Fear-avoidance of pain influences physical impairment and is more strongly associated with functional disability than pain severity.[66–68] In contrast, progressive increase in activity through exercise has been shown to result in significant benefits in pain, disability, physical impairment, and psychological distress for low back pain patients.[69] In light of the robust relation between coping behaviors and pain, behavioral and psychosocial interventions hold great promise in reducing pain intensity and pain-related functional disability in chronic pain conditions such as low back pain.[70]

 

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Dr. Alex Jimenez’s Insight

Different sensory nerve fibers respond to different stimulations and produce different chemical reactions which determine how different sensations are interpreted. Special pain receptors, known as nociceptors, activate when there has been trauma from an injury or even through potential damage to the human body. This impulse, immediately sends a signal through the nerve and into the spinal cord, eventually reaching all the way to the brain. The role of the spinal cord in pain perception is also to simultaneously direct impulses to the brain and back down the spinal cord to the region of the injury. These are referred to as reflexes. However, the pain signal still needs to continue to the brain so it can respond accordingly. The brain will assess the type of pain and where it came from, triggering a healing response as well as a variety of other bodily responses to address the pain signal effectively. In the case of chronic pain, pain perception may not be working accordingly along any of the pathways mentioned above. Treatment can help improve chronic pain as well as manage the painful symptoms.

 

Conclusion

 

The foregoing review attests to the multidimensionality of pain. Pain is a biopsychosocial experience that goes well beyond mere nociception. In this regard, identification of the physical pathology at the site of injury is necessary but not sufficient to explicate the complex process by which somatosensory information is transformed into the physiological, cognitive, affective, and behavioral response labeled as pain. Indeed, in the case of chronic low back pain, the magnitude of tissue damage may be out of proportion to the reported pain experience, there may be no remaining structural impairment, and physical signs that have a predominantly nonorganic basis are likely to be present.[71,72] In this and other chronic conditions, to consider such pain as malingering or somatization would be to grossly oversimplify the matter. Pain, whether linked with injured tissue, inflammation, or functional impairment, is mediated by processing in the nervous system. In this sense, all pain is physical. Yet, regardless of its source, pain may result in hypervigilance, threat appraisals, emotional reactions, and avoidant behavior. So in this sense, all pain is psychological. Our nomenclature and nosology struggle to categorize the pain experience, but in the brain, all such categories are moot. Pain is fundamentally and quintessentially a psychophysiological phenomenon.

 

Key Points

 

  • Pain is a biopsychosocial experience that goes well beyond mere nociception. In this regard, identification of the physical pathology at the site of injury is necessary but not sufficient to explicate the complex process by which somatosensory information is transformed into the physiological, cognitive, affective, and behavioral response labeled as pain
  • In the case of chronic low back pain, the magnitude of tissue damage may be out of proportion to the reported pain experience, there may be no remaining structural impairment, and physical signs that have a predominantly nonorganic basis are likely to be present.
  • Pain, whether linked with injured tissue, inflammation, or functional impairment, is mediated by processing in the nervous system. In this sense, all pain is physical. Yet, regardless of its source, pain may result in hypervigilance, threat appraisals, emotional reactions, and avoidant behavior. So in this sense, all pain is psychological.
  • Our nomenclature and nosology struggle to categorize the pain experience, but in the brain, all such categories are moot. Pain is fundamentally and quintessentially a psychophysiological phenomenon.

 

Acknowledgements

 

ELG was supported by grant DA032517 from the National Institute on Drug Abuse in the preparation of this manuscript.

 

Footnotes

 

Ncbi.nlm.nih.gov/pmc/articles/PMC3438523/

 

Plants as Medicine: Are Cannabinoids the Next Breakthrough in Plant Medicine?

 

If you’ve ever eaten a carrot, then you have consumed a cannabinoid. Most people associate cannabinoids with marijuana. The most commonly recognized cannabinoid is tetrahydrocannabinol, or THC, the chemical in marijuana that causes feelings of euphoria. Until recently, scientists had identified cannabinoids just in the cannabis plant, commonly called hemp or marijuana. Current research, however, has found cannabinoids in several plants, including clove, black pepper, Echinacea, ginseng and broccoli as well as carrots. No matter how many carrots you crunch, however, they will not get you too high. But understanding how the cannabinoids in different plants affect the human body may contribute to important health discoveries.

 

Plants as Medicine

 

Some of the most appreciated modern drugs were developed by analyzing plants used in conventional medicine. Researching the chemicals in these plants led to the discovery of life-saving drugs and furthered our knowledge of how the human body works. For instance, the foxglove plant introduced us to digoxin and digitoxin, two important heart medications.[1] As well as the Pacific yew contains paclitaxel, which can be used in the treatment of many cancers.[1] Throughout history, people have been especially adept at finding plants which either increase pleasure or reduce pain. Caffeine from tea and tea provides energy and keeps us awake, while smoking from tobacco is believed to be concurrently stimulating and relaxing, likely explaining why tobacco remains popular despite the known health risks of smoking.[2]

 

Several sorts of pain-relieving drugs originated with plants:

 

Opiates

 

By analyzing opium from the poppy plant, scientists discovered opiate receptors in the human body and their role in pain control, which led to the development of morphine, codeine, and other opiate drugs and/or medications.[3]

 

Aspirin

 

As far back as ancient Egypt, health practitioners used tea made from the willow tree to decrease pain and fever. It took tens of thousands of years for scientists to find and isolate the active chemical, or the fatty acid, which led to the discovery of aspirin and from there, finding insights into the processes involved with inflammation.[4]

 

Anesthetics

 

The leaves of the coca plant were used from the ancient Incan Empire from South America to deal with headaches, wounds and fractures. Coca eventually yielded the drug cocaine, which is a drug of misuse and abuse, but also an effective anesthetic. Recognizing how cocaine blocked pain led to the development of common anesthetics such as lidocaine, famous for making invasive dental procedures more comfortable.[5]

 

Cannabis and Human Health

 

Such as other medicinal plants, the cannabis species has been used for centuries. A Chinese text from the year AD 1 records the usage of hemp to treat more than 100 ailments dating back to 2737 BC.[6] Afterwards, the flowering tops of the Cannabis plant began to be cultivated for their psychoactive properties, while a different selection of the plant was increased as industrial hemp to be used in producing garments, paper, biofuels, foods, and other products.

 

Because of the controversy surrounding marijuana as a recreational drug, researchers have not been able to readily study the effects of the many non-THC ingredients in Cannabis. Although THC was identified from the 1940s, it was not until 50 years after that studies demonstrated that individuals, and nearly all animals,  have an inner system of cannabinoid receptors. What is more, we really make cannabinoids in our bodies, known as endocannabinoids, that act on these receptors.[7]

 

This physiological system is called the endocannabinoid system, or ECS, and new science appears almost daily about its function in human health. The ECS is involved in multiple functions, such as pain feeling, hunger, memory, and disposition. If you’ve ever stubbed your toe, digested an apple, then forgotten a password, or happily smile, then your ECS was involved, little did you know.

 

The discovery of the ECS gave science and medicine a whole new outlook about the organic compounds being identified in Cannabis. Researchers started referring to these chemicals as phytocannabinoids, from the work “phyto” for plant. More than 80 phytocannabinoids have been found in hemp and marijuana. THC is only one of many compounds being studied for the advantages they can provide.[8]

 

Past Cannabis and THC

 

Now that many different crops are known to contain chemicals that influence the ECS, phytocannabinoids are no longer just associated with the cannabis plant.[9] Chances are you have some source of phytocannabinoids in your diet right now. But it might be a small quantity, rather than all of phytocannabinoids interact strongly with the ECS.

 

What exactly do we know up to now? Current research shows that a number of the phytocannabinoids in hemp, clove, and black pepper can encourage the ECS to promote relaxation, decrease nerve distress, and improve digestive health. As these compounds don’t possess the mind-altering effects of THC, more individuals are likely to flip to phytocannabinoids to acquire their health benefits without having high.[10] Information referenced from the National Center for Biotechnology Information (NCBI). The scope of our information is limited to chiropractic as well as to spinal injuries and conditions. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at 915-850-0900 .

 

Curated by Dr. Alex Jimenez

 

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Additional Topics: Back Pain

 

Back pain is one of the most prevalent causes for disability and missed days at work worldwide. As a matter of fact, back pain has been attributed as the second most common reason for doctor office visits, outnumbered only by upper-respiratory infections. Approximately 80 percent of the population will experience some type of back pain at least once throughout their life. The spine is a complex structure made up of bones, joints, ligaments and muscles, among other soft tissues. Because of this, injuries and/or aggravated conditions, such as herniated discs, can eventually lead to symptoms of back pain. Sports injuries or automobile accident injuries are often the most frequent cause of back pain, however, sometimes the simplest of movements can have painful results. Fortunately, alternative treatment options, such as chiropractic care, can help ease back pain through the use of spinal adjustments and manual manipulations, ultimately improving pain relief.

 

 

 

blog picture of cartoon paperboy big news

 

EXTRA IMPORTANT TOPIC: Low Back Pain Management

 

MORE TOPICS: EXTRA EXTRA: Chronic Pain & Treatments

 

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Close Accordion
Depression and Anxiety in Chronic Pain

Depression and Anxiety in Chronic Pain

Everyone will experience some type of pain throughout their lifetime, however, for those people who have anxiety or depression, pain can become especially intense and it can be challenging to treat. Individuals experiencing depression, for instance, often experience more severe and long-term pain than other individuals. The overlap of anxiety, depression, and pain is very evident in chronic pain and sometimes debilitating syndromes, such as fibromyalgia, irritable bowel syndrome, low back pain, headaches, and nerve pain. Psychiatric disorders not only bring about pain intensity but also contribute to increased risk of disability.

 

Researchers once believed that the connection between pain, anxiety, and depression resulted mostly from psychological rather than biological factors. Chronic pain can lead to depression, and also, major depression may feel emotionally painful. But as researchers have learned more about how the brain works, and how the nervous system interacts with other areas of the body, they’ve found that pain shares some biological mechanisms with depression and anxiety. Therapy is challenging when pain overlaps with anxiety or depression. Focus on pain can conceal both the clinician’s and patient’s awareness that a psychiatric disorder is also present. Even when the two types of problems are properly diagnosed, they can be difficult to treat.

 

Depression and Anxiety in Pain

 

Abstract

 

  • Mood disorders, especially depression and anxiety, play an important role in the exacerbation of pain perception in all clinical settings.
  • Depression commonly occurs as a result of chronic pain and needs treating to improve outcome measures and quality of life.
  • Anxiety negatively affects thoughts and behaviours which hinders rehabilitation.
  • Anxiety and depression in acute hospital settings also negatively affect pain experience and should be considered in both adults and children.
  • Poor pain control and significant mood disorders perioperatively contribute to the development of chronic postoperative pain.

 

Introduction

 

Pain concepts have moved radically away from the early nociceptive Cartesian principle, where a specific lesion in the body is experienced as pain by the brain. This has been replaced by the widely accepted biopsychosocial model, where tissue damage, psychology and environmental factors all interact to determine pain experience. The IASP’s definition of pain as “an unpleasant sensory or emotional experience associated with tissue damage…” further emphasises the significant role of mood and emotions for pain perception. Among these, depression and anxiety have been implicated as important contributors to the experience of pain, and have been extensively studied.

 

Depression

 

Depression is characterised by a pervasive low mood, loss of interest in usual activities and diminished ability to experience pleasure. Within this definition there exists a whole spectrum of severity, symptoms and signs together with their classifications. The DSM-IV (Diagnostic and Statistical Manual) is a common diagnostic classification system for psychiatric conditions and is also used for research, insurance and administration[1]. A common prerequisite for diagnosis of depression or other psychiatric disorders is that any symptoms experienced should result in clinically significant distress or impairment of social, occupational, or other important areas of functioning.

 

The Scale of the Problem

 

The association of chronic pain with depression has been of great interest in the past few decades. Chronic musculoskeletal pain patients have higher depression than individuals without pain in a general population study[2]. A third of patients in a pain clinic population had ‘major depression’ according to the criteria of the Diagnostic and Statistical Manual (DSM IV) following structured interviews[3]. The presence of pain can make recognition of depression more difficult, even though increased severity of pain worsens depressive symptoms[4].

 

Diagnostic and Assessment Issues

 

The association between depression and chronic pain, though widely accepted, is marred by diagnostic difficulties. In research for ‘depression’ various definitions exist in studies, leading to a variety of assessment methods, including self report instruments, chart reviews and structured or unstructured clinical interviews. Many studies relating to depression and chronic pain include heterogenous groups of patients with different chronic pain conditions and unspecified diagnostic criteria for depression. This clearly questions the validity of studies.

 

In the clinical setting many tools exist for the assessment of the severity and nature of depression. In chronic pain, the Zung Self-Rating Depression Scale (SDS), Beck’s Depression Inventory (BDI) and Depression, Anxiety and Stress Scale (DASS) are commonly used. The SDS and DASS in particular, have shown high internal consistency and validity in chronic pain patients. However many criteria for depression, like fatigue, insomnia and weight change, are symptoms attributable to chronic pain itself. The DSM-IV places emphasis on weight loss, appetite change and fatigue on diagnosis, and the Beck’s Depression Inventory and Zung Self-Rating Depression Scales also include a substantial number of such somatic items. Such ‘criterion contamination’ may lead to overestimation of depression. The DASS excludes such somatic items and is thought to provide a more accurate assessment of depression, especially in chronic pain patients[5]. Another questionnaire designed specifically for chronic pain patients is the Depression, Anxiety and Positive Outlook Scale (DAPOS). This also contains no somatic items and includes measures of optimism[6].

 

These points illustrate the unique difficulty present in the study of depression in chronic pain patients. It is not surprising that meta-analyses or systematic reviews in this area are relatively scarce. Just as depression is not a single entity but a spectrum, chronic pain patients are also a very heterogenous group of patients. All these have to be borne in mind when reviewing papers and studies of depression in chronic pain.

 

Depression and Pain: Chicken and Egg?

 

Physiological similarities exist between chronic pain and depression. For example, noradrenaline and serotonin involved in the pathophysiology of depression also coincide with the anatomical ‘descending inhibition’ of pain perception. These two neurotransmitters act in the limbic system and periaqueductal areas to modulate incoming pain stimuli. Antidepressants working through these neurotransmitters are also analgesic regardless of the presence of depression.

 

This leads to the question of whether depression follows the establishment of chronic pain or whether chronic pain is a manifestation of a form of depression or a spectrum thereof. Some evidence exists for both views. For example, patients with preexisting depression were found to be more likely to develop chest pain and headaches in a three year period[7]. Conversely a review of forty studies supported the notion that depression is a consequence of protracted pain[8]. The ‘diathesis-stress’ model for this conundrum is now growing in acceptance which supports that depression is a sequalae of chronic pain. Accordingly people with a psychological predisposition (diathesis), superimposed with the stresses of chronic pain go on to develop clinical depression.

 

Chronic pain is also associated with anxiety disorders (discussed below), somatoform disorders, substance use disorders, and personality disorders. As with depression, pre-existing, semidormant characteristics of the individual before the onset of chronic pain are activated and exacerbated by the stress of chronic pain, eventually resulting in diagnosable psychopathology[9]. Psychosocial elements which predict chronic pain and disability (yellow flags) used in clinical practice may well fit into this construct.

 

Yellow Flags are psychosocial factors that increase the risk of developing or perpetuating long-term disability and work loss associated with low back pain. Such include:

 

  • Attitudes and Beliefs about back pain. The belief that pain is harmful or disabling resulting in fear-avoidance behaviour.
  • Behaviours. Use of extended rest, disproportionate ‘downtime’.
  • Compensation Issues. Lack of financial incentive to return to work.
  • Diagnosis and Treatment. Health professional sanctioning disability, not providing interventions that will improve function.
  • Emotions. Fear of increased pain with activity or work.
  • Family and Work. Over-protective partner/spouse, emphasising fear of harm or encouraging catastrophising. Manual work and job dissatisfaction.

 

The Costs of Depression in Pain

 

Social functioning, work and physical activities are all decreased whilst utilisation of medical services increases if depression coexists with pain[10]. Motivation and compliance with treatment is also affected[11]. Such negative outcomes leave little doubt as to the quality of life of such patients. Clearly pain and depression should not be seen as separate dimensions but as interactive in nature. Attempting to treat pain without considering depression is likely to be a futile venture.

 

Anxiety in Chronic Pain

 

Anxiety is a physiological state characterized by cognitive, somatic, emotional, and behavioral components producing fear and worry. Anxiety is often accompanied by physical sensations such as heart palpitations and shortness of breath whilst the cognitive component entails expectation of a diffuse and certain danger. As with depression, anxiety disorders are categorised in the DSM-IV, with subtypes including generalised anxiety disorder (GAD), panic disorder and phobias. GAD is the most commonly diagnosed anxiety disorder in chronic pain populations. The coexistence of pain and anxiety is perhaps not surprising: Both signal impending danger and the necessity for action which confer survival value to the individual.

 

Anxiety disorders are second only to depression in psychological comorbidity in chronic pain populations. Whilst anxiety is a normal response in everyone, clinical anxiety results in increased intensity and prolongation of the feelings of dread that interfere with normal functioning. Measurements of anxiety with chronic pain also show a strong association: as with depression. One such study showed a doubling in the prevalence of anxiety disorders compared to the general population[12]. Anxiety is thought to be an important mediator in the cognitive constructs of catastrophising, hypervigilance and fear avoidance in the exacerbation of pain experiences.

 

  • Catastfophising is ‘dwelling on the worst possible outcomes’. It is associated with higher disability and pain severity and is an important cognitive measure and prognostic indicator in chronic pain patients.
  • Hypervigilance in pain is the increased attendance to pain and decreased ability to distract oneself from pain-related stimuli.
  • Fear avoidance is the avoidance of movement or activities based on fear of pain or re-injury. This is especially counterproductive for physical rehabilitation and is termed ‘kinesophobia’.

 

Measurement of Anxiety in Pain

 

As with depression many measures of anxiety states exist. The State-Trait Anxiety Inventory questionnaire is a well-validated tool used in general psychology but has also been used in pain clinics. For chronic pain, more specific measures of anxiety-related to cognitive and behavioural variables have been designed. Such an instrument is the Pain Anxiety Symptoms Scale (PASS) which measures behavioural responses to pain[13]. The Fear of Pain Inventory measures degree of fear in hypothetical pain inducing situations[14]. These are more useful than general anxiety measurements and give more specific information in relation to the pain experienced. The DASS and DAPOS used for depression also measure anxiety.

 

Anxiety and Depression Coexist

 

Despite their differences in symptoms and classification, depression and anxiety seem to exist concurrently to a surprisingly frequent extent. In psychiatry, terms like ‘agitated depression’ have been coined for a state of depression that presents as anxiety which includes restlessness, insomnia and nonspecific panic.

 

Even mild anxiety symptoms can have a major impact on the course of a depressive illness. Depressed or bipolar patients with lifetime panic symptoms have significant delays in remission for depression[15]. To this end, the presence of both depression and anxiety make treatment of pain more challenging but the presence of one should alert rather than deter the diagnosis of the other.

 

Treatment of Depression and Anxiety

 

Mainstays of treatment of depression and anxiety are psychological and pharmacological. Whilst the scope of these is well beyond this article, it is worth noting that cognitive behavioural therapy, which addresses depression and anxiety, has very good evidence for efficacy in chronic pain patients[16]. Important concepts of CBT are also incorporated into Pain Management Programs for delivery to patients with different types of pain.

 

Depression and Anxiety in Acute Pain

 

Hitherto depression and anxiety have only been discussed in a chronic setting. Current multidimensional concepts of pain are equally important in the acute setting. Apart from the degree of surgical insult to tissue, psychological and environmental factors influence acute pain experience to a high degree[17].

 

Preoperative anxiety is correlated with higher pain intensity postoperatively for a variety of operations. In the hospital setting, anxiety is worsened by sleep deprivation in the postoperative period due to interruptions in the wards for observations, other patients and medications. This vicious circle is exacerbated by fear of complications, loss of control and helplessness. Admission to hospital and having an operation is a highly stressful event for most and that is often forgotten by professionals who are frequently involved in perioperative care. Preoperative depression also increases pain intensity, opioid requirements by any route and number of demands from the PCAS (Patient controlled analgesia system) in the postoperative period. Higher levels of dissatisfaction with analgesia also occur if depression coexists[18].

 

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Dr. Alex Jimenez’s Insight

From headaches to muscle tension and body soreness, pain may be all too familiar for individuals who suffer from anxiety and depression. However, many research studies have demonstrated that chronic pain, such as that resulting from conditions like arthritis or fibromyalgia, may in turn lead to a variety of mental health issues. Both anxiety and depression have been implicated to be fundamental contributors in the exacerbation of as well as in the perception of pain. As a result, many healthcare professionals have developed a treatment approach based on therapeutic strategies to help manage symptoms of anxiety and depression. By first controlling these symptoms, many doctors can safely and effectively help in the management of chronic pain. Recent research studies have found a connection between the endocannabinoid system and the management of chronic pain, as well as anxiety and depression.

 

Treatment Strategies

 

Strategies used include procedural and sensory information, relaxation and attentional strategies, hypnosis and cognitive behavioural treatments. The use of anxiolytic drugs on the morning of procedure or hypnotics the night before are also widespread.

 

Combination of procedural information of the surgery together with expected sensations felt by the patient postoperatively have yielded Level I evidence (evidence obtained from at least one properly designed randomised controlled trial) for benefits on pain perception[19]. Another meta-analysis on giving information regarding the conduct of surgical treatment showed decreased hospital stay[20].

 

Relaxation techniques involve teaching patients calming methods, including breathing techniques, self hypnosis and muscle relaxation.

 

This has been verified in a metanalysis providing Level I evidence for reducing pain as well as blood pressure and pulse[21]. Hypnosis and attention diversion from pain has also garnered evidence for effectiveness. A ‘moderate to large’ effect size on reduction of pain has been shown in yet another meta-analysis of hypnosis, in both laboratory and clinical participants[22].

 

Psychological interventions for children are also increasingly recognized and being used. Cognitive behavioural strategies are shown to be effective in procedural related pain in children and adolescents[23].

 

Techniques used involve breathing exercises, distraction and incentives. These techniques involve psychologists, parents and medical staff.

 

Even in the intensive care, mood disorders need attention. Mechanically ventilated patients without surgery or trauma are known to experience pain, which leads to increased anxiety and adverse physiological effects[24]. Analgesia and sedation thus need to be adjusted with evaluation of pain in mind.

 

There is very good evidence to implicate mood disorders, especially anxiety, in worsening pain experience in acute surgical or procedural situations. Evidence extends to oncology and paediatric patients also. As a basic strategy, careful explanation and allaying of fears should be practiced by any healthcare professional involved in interventions. This can be combined with some of the psychological techniques described above. There is a greater wealth of high level evidence for mood disorders in acute compared to chronic pain. Shorter time frames of studies and greater numbers of suitable patients for recruitment are contributory factors to this.

 

Bridging the Gap

 

What causes acute pain to become chronic? Many patients who do develop chronic pain can pin down an episode of acute pain as a precipitant[25]. Some risk factors are known. Surgical procedures like amputation, thoracotomy and radical mastectomy are notorious for causing chronic pain postoperatively. Psychosocial contributors like ‘psychological vulnerability’ preoperatively, and depression and anxiety postoperatively have been implicated[26]. Treatment or attenuation of anxiety and depression could thus be a vital component of perioperative pain control when considering longer term outcomes. Increased pain intensity is also a risk factor for chronic pain development. Treating acute pain is therefore vital for preventing chronicity.

 

Conclusion

 

Pain is one of the commonest symptoms for which patients seek medical attention. Depression and anxiety symptoms are important to consider not only in primary healthcare settings and pain clinics but also in hospital and palliative care settings. They must be borne in mind not only in adults but in children too. The education of patients of the role of depression and anxiety in pain is paramount, but awareness of these issues by healthcare professionals in all disciplines is the preceding and necessary step for good quality patient management.

 

The Endocannabinoid System

 

What is the ECS?

 

The significance of the ECS, or the endocannabinoid system, has just recently been realized and is currently being referred to as the most essential body system which you may have never heard of. Although the ECS is one of the principal systems in the body, it is not an isolated structural system like the nervous system or the vascular system. Instead, the endocannabinoid system is broadly dispersed throughout the human body and is composed of its own receptor sites, similar to little docking stations, which can in turn be found on nearly every organ in the human body.

 

What does the ECS do?

 

The ECS is the human body’s main regulatory system. It’s like an inner balancing mechanism, constantly keeping a wide range of bodily functions in equilibrium. The body produces its own endocannabinoids which modulate different biological processes throughout the body, providing these endocannabinoids with a variety of ranging consequences on everything from fertility to pain. Cannabinoid receptors can be found in the brain, nervous system, GI, or gastrointestinal, tract, bones, immune system, skin, and nearly every other organ in the body. Furthermore, the ECS helps regulate:

 

  • Appetite
  • Bone health
  • Caloric metabolism
  • Fertility
  • Immune function
  • Inflammation
  • Mood
  • Memory
  • Pain sensation
  • Skin health
  • Sleep
  • Stress response

 

Are There Any Plant Sources of Cannabinoids?

 

To put it simply, yes. We now know that many animals, from fish to birds to mammals, have their own ECS. Additionally, it’s well understood that while humans make their own cannabinoids which interact with the ECS, known as endocannabinoids, there are also compounds which interact with the ECS that are found in an assortment of plants and foods, known as phytocannabinoids. These plant-based cannabinoids either directly attach to, and also have an effect on, cannabinoid receptors, or they may even have an influence on the metabolism of endocannabinoids produced within the body. These can ultimately slow down their destruction, keeping them within the body longer.

 

Cannabis cultivated as hemp contains numerous phytocannabinoids, including tetrahydrocannabinolic acid, or THCA, cannabidiol, or CBD, tetrahydrocannabivarin, or THCV, cannabigerol, or CBG, cannabinol, or CBN, among many others. Common non-cannabis plants which contain phytocannabinoids include black pepper, clove, Echinacea, green tea, Panax ginseng, and black truffles. Within nature, chemical substances rarely act in isolation, and this is particularly true of both phytocannabinoids, which actually work together in a carefully coordinated manner.

 

What is the Distinction Between Hemp and Marijuana?

 

Hemp and marijuana are basically different cultivars of the same plant, Cannabis sativa L. A cultivar is a plant type that has been made or cultivated through a process of selective breeding. Marijuana is a sort of cannabis that has been bred to concentrate high levels of the psychoactive chemical, THC, or tetrahydrocannabinoid, for recreational and medicinal use, often containing about 18 percent  of THC. Conversely, hemp is a version of cannabis that is primarily utilized in clothing, paper, biofuels, bio-plastics, dietary supplements, cosmetics, and foods. Hemp contains less than 0.3 percent of THC as measured in the dried flowering tops.

 

In conclusion, recent research studies have found a strong connection between the psychology of chronic pain, especially the relationship between anxiety, depression and pain. For individuals with mental health issues, chronic pain can be a common symptoms which may or may not be directly associated with their specific condition. Fortunately, patients can successfully manage their anxiety, depression and chronic pain through a variety of treatments. The purpose of the article above is to demonstrate the connection between anxiety, depression and chronic pain as well as to discuss the significance of the endocannabinoid system, or ECS, and the use of cannabinoids as chronic pain treatment. Information referenced from the National Center for Biotechnology Information (NCBI). The scope of our information is limited to chiropractic as well as to spinal injuries and conditions. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at 915-850-0900 .

 

Curated by Dr. Alex Jimenez

 

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Additional Topics: Back Pain

 

Back pain is one of the most prevalent causes for disability and missed days at work worldwide. As a matter of fact, back pain has been attributed as the second most common reason for doctor office visits, outnumbered only by upper-respiratory infections. Approximately 80 percent of the population will experience some type of back pain at least once throughout their life. The spine is a complex structure made up of bones, joints, ligaments and muscles, among other soft tissues. Because of this, injuries and/or aggravated conditions, such as herniated discs, can eventually lead to symptoms of back pain. Sports injuries or automobile accident injuries are often the most frequent cause of back pain, however, sometimes the simplest of movements can have painful results. Fortunately, alternative treatment options, such as chiropractic care, can help ease back pain through the use of spinal adjustments and manual manipulations, ultimately improving pain relief.

 

 

 

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EXTRA IMPORTANT TOPIC: Low Back Pain Management

 

MORE TOPICS: EXTRA EXTRA: Chronic Pain & Treatments

 

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References
1. American Psychiatric Association. DSM –IV-TRSourcebook 2000.
2. Magni G, Marchetti M, Moreschi C, Merskey H, Luchini SR. Chronic musculoskeletal pain and depression symptoms in the national health and nutrition examination I. Epidemiologic follow-up studyPain 1993; 53(2): 163–8. [PubMed]
3. Wilson KG, Eriksson MY, Joyce L, Mikail SF, Emery PC. Major depression and insomnia in chronic painClin J Pain 2002; 18: 77–83. [PubMed]
4. Bair MJ, Robinson RL, Katon W, Kroenke K. Depression and pain comorbidity: a literature reviewArch Intern Med 2003; 163(20): 2433–45. [PubMed]
5. Taylor R, Lovibond PF, Nicholas MK, Cayley C, Wilson PH. The utility of somatic items in the assessment of depression in patients with chronic pain: a comparison of the zung self-rating depression scale and the depression anxiety stress scales in chronic pain and clinical and community samplesClin J Pain 2005; 21(1): 91–100. [PubMed]
6. Pincus T, Williams AC, Vogel S, Field A. The development and testing of the depression, anxiety, and positive outlook scale (DAPOS)Pain 2004; May 109 (1–2): 181–8. [PubMed]
7. von Korff M, Le Resche L, Dworkin SF. First onset of common pain symptoms: a prospective study of depression as a risk factorPain 1993; 55(2): 251–8. [PubMed]
8. Fishbain DA, Cutler R, Rosomoff HL, Rosomoff RS. Chronic pain-associated depression: antecedent or consequence of chronic pain? A reviewClin J Pain 1997; 13(2): 116–37. [PubMed]
9. Dersh J, Polatin PB, Gatchel RJ. Chronic pain and psychopathology: research findings and theoretical considerationsPsychosom Med 2002; 64(5): 773–86. [PubMed]
10. Worz R. Pain in depression, depression in painPain Clinical Updates 2003; IASP Vol XINo. 5.
11. Kerns RD, Haythornthwaite JA. Depression among chronic pain patients: cognitive-behavioural analysis and effect on rehabilitation outcomeJ Consult Clin Psychol 1988; 56(6): 870–6. [PubMed]
12. McWilliams LA, Cox BJ, Enns MW. Mood and anxiety disorders associated with chronic pain: an examination in a nationally representative samplePain 2003; 106(1–2): 127–33. [PubMed]
13. McCracken LM, Zayfert C, Gross RT. The pain anxiety symptoms scale: development and validation of a scale to measure fear of painPain 1992; 50(1): 67–73. [PubMed]
14. McNeil D, Rainwater A. Development of the fear of pain questionnaire – IIIJ Behav Med 1998; 21(4): 389–410. [PubMed]
15. Frank E, Prien RF, Jarrett RB, Keller MB, Kupfer DJ, Lavori PL, et al. Conceptualization and rationale for consensus definitions of terms in major depressive disorder. Remission, recovery, relapse and recurrenceArch Gen Psychiatry 1991; 48(9): 851–5. [PubMed]
16. Morley S, Eccleston C, Williams A. Systematic review and meta-analysis of randomized controlled trials of cognitive behaviour therapy and behaviour therapy for chronic pain in adults, excluding headachePain 1999; 80(1–2): 1–13. [PubMed]
17. Siddall PJ, Cousins MJ. Persistent pain as a disease entity: implications for clinical managementAnesth Analg 2004; 99(2): 510–20. [PubMed]
18. ANZCA Acute Pain Management: Scientific Evidence: Australian & New Zealand College of Anaesthetists; (2nd Ed.) 2005.
19. Suls J, Wan CK. Effect of sensory and procedural information on coping with stressful medical procedures and pain. A meta-analysisJ Consult Clin Psychol 1989; 57: 372–9. [PubMed]
20. Johnston M, Vogele C. Benefits of psychological preparation for surgery: a meta-analysisAnn Behav Med 1993; 15(4): 245–56.
21. Luebert K, Hahme B, Hasenbring M. The effectiveness of relaxation training in reducing treatment-related symptoms and improving emotional adjustment in acute non-surgical cancer treatment. A meta-analytical reviewPsychooncology 2001; 10(6): 490–502. [PubMed]
22. Montgomery GH, DuHamel KN, Redd WH. A meta analysis of hypnotically induced analgesia: how effective is hypnosis? Int J Clin Exp Hypn 2000; 48(2): 138–53. [PubMed]
23. Powers SW. Empirically supported treatment in pediatric psychology: procedure-related painJ Pediatr Psychol 1999; 24: 131–45. [PubMed]
24. Schweickert WD, Kress JP. Strategies to optimize analgesia and sedationCrit Care 2008; 12(Suppl. 3): S6. [PMC free article] [PubMed]
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Close Accordion
Biochemistry Of Pain

Biochemistry Of Pain

Biochemistry of Pain: All pain syndromes have an inflammation profile. An inflammatory profile can vary from person to person and can also vary in one person at different times. The treatment of pain syndromes is to understand this inflammation profile. Pain syndromes are treated medically, surgically or both. The goal is to inhibit/suppress the production of inflammatory mediators. And a successful outcome is one that results in less inflammation and of course less pain.

Biochemistry Of Pain

Objectives:

  • Who are the key players
  • What are the biochemical mechanisms?
  • What are the consequences?

Inflammation Review:

Key Players

biochemistry of pain el paso tx.

biochemistry of pain el paso tx.

biochemistry of pain el paso tx.

biochemistry of pain el paso tx.Why Does My Shoulder Hurt? A Review Of The Neuroanatomical & Biochemical Basis Of Shoulder Pain

ABSTRACT

If a patient asks ‘why does my shoulder hurt?’ the conversation will quickly turn to scientific theory and sometimes unsubstantiated conjecture. Frequently, the clinician becomes aware of the limits of the scientific basis of their explanation, demonstrating the incompleteness of our understanding of the nature of shoulder pain. This review takes a systematic approach to help answer fundamental questions relating to shoulder pain, with a view to providing insights into future research and novel methods for treating shoulder pain. We shall explore the roles of (1) the peripheral receptors, (2) peripheral pain processing or ‘nociception’, (3) the spinal cord, (4) the brain, (5) the location of receptors in the shoulder and (6) the neural anatomy of the shoulder. We also consider how these factors might contribute to the variability in the clinical presentation, the diagnosis and the treatment of shoulder pain. In this way we aim to provide an overview of the component parts of the peripheral pain detection system and central pain processing mechanisms in shoulder pain that interact to produce clinical pain.

INTRODUCTION: A VERY BRIEF HISTORY OF PAIN SCIENCE ESSENTIAL FOR CLINICIANS

The nature of pain, in general, has been a subject of much controversy over the past century. In the 17th century Descartes’ theory1 proposed that the intensity of pain was directly related to the amount of associated tissue injury and that pain was processed in one distinct pathway. Many earlier theories relied upon this so-called ‘dualist’ Descartian philosophy, seeing pain as the consequence of the stimulation of a ‘specific’ peripheral pain receptor in the brain. In the 20th century a scientific battle between two opposing theories ensued, namely specificity theory and pattern theory. The Descartian ‘specificity theory’ saw pain as a specific separate modality of sensory input with its own apparatus, while ‘pattern theory’ felt that pain resulted from the intense stimulation of non-specific receptors.2 In 1965, Wall and Melzack’s 3 gate theory of pain provided evidence for a model in which pain perception was modulated by both sensory feedback and the central nervous system. Another huge advance in pain theory at around the same time saw the discovery of the specific mode of actions of the opioids.4 Subsequently, recent advances in neuroimaging and molecular medicine have vastly expanded our overall understanding of pain.

So how does this relate to shoulder pain? Shoulder pain is a common clinical problem, and a robust understanding of the way in which pain is processed by the body is essential to best diagnose and treat a patient’s pain. Advances in our knowledge of pain processing promise to explain the mismatch between pathology and the perception of pain, they may also help us explain why certain patients fail to respond to certain treatments.

BASIC BUILDING BLOCKS OF PAIN

Peripheral sensory receptors: the mechanoreceptor and the ‘nociceptor’

There are numerous types of peripheral sensory receptors present in the human musculoskeletal system. 5 They may be classified based on their func­tion (as mechanoreceptors, thermoreceptors or nociceptors) or morphology (free nerve endings or different types of encapsulated receptors).5 The dif­ferent types of receptor can then be further subclas­sified based on the presence of certain chemical markers. There are significant overlaps between dif­ferent functional classes of receptor, for example

Peripheral Pain Processing: ‘Nociception’

Tissue injury involves a variety of inflammatory mediators being released by damaged cells including bradykinin, histamine, 5-hydroxytryptamine, ATP, nitric oxide and certain ions (K+ and H+). The activation of the arachidonic acid pathway leads to the production of prostaglandins, thromboxanes and leuko- trienes. Cytokines, including the interleukins and tumor necrosis factor α, and neurotrophins, such as nerve growth factor (NGF), are also released and are intimately involved in the facilitation of inflammation.15 Other substances such as excitatory amino acids (glutamate) and opioids (endothelin-1) have also been implicated in the acute inflammatory response.16 17 Some of these agents may directly activate nociceptors, while others bring about the recruitment of other cells which then release further facilitatory agents.18 This local process resulting in the increased responsiveness of nociceptive neurons to their normal input and/or the recruitment of a response to normally subthreshold inputs is termed ‘peripheral sensitization’. Figure 1 summarizes some of the key mechanisms involved.

biochemistry of pain el paso tx.NGF and the transient receptor potential cation channel subfamily V member 1 (TRPV1) receptor have a symbiotic relationship when it comes to inflammation and nociceptor sensitization. The cytokines produced in inflamed tissue result in an increase in NGF production.19 NGF stimulates the release of histamine and serotonin (5-HT3) by mast cells, and also sensitizes nociceptors, possibly altering the properties of Aδ fibers such that a greater proportion become nociceptive. The TRPV1 receptor is present in a subpopulation of primary afferent fibers and is activated by capsaicin, heat and protons. The TRPV1 receptor is synthesized in the cell body of the afferent fibre, and is transported to both the peripheral and central terminals, where it contributes to the sensitivity of nociceptive afferents. Inflammation results in NGF production peripherally which then binds to the tyrosine kinase receptor type 1 receptor on the nociceptor terminals, NGF is then transported to the cell body where it leads to an up regulation of TRPV1 transcription and consequently increased nociceptor sensitivity.19 20 NGF and other inflammatory mediators also sensitize TRPV1 through a diverse array of secondary messenger pathways. Many other receptors including cholinergic receptors, γ-aminobutyric acid (GABA) receptors and somatostatin receptors are also thought to be involved in peripheral nociceptor sensitivity.

A large number of inflammatory mediators have been specifically implicated in shoulder pain and rotator cuff disease.21–25 While some chemical mediators directly activate nociceptors, most lead to changes in the sensory neuron itself rather than directly activating it. These changes may be early post- translational or delayed transcription dependent. Examples of the former are changes in the TRPV1 receptor or in voltage- gated ion channels resulting from the phosphorylation of membrane-bound proteins. Examples of the latter include the NGF-induced increase in TRV1 channel production and the calcium-induced activation of intracellular transcription factors.

Molecular Mechanisms Of Nociception

The sensation of pain alerts us to real or impending injury and triggers appropriate protective responses. Unfortunately, pain often outlives its usefulness as a warning system and instead becomes chronic and debilitating. This transition to a chronic phase involves changes within the spinal cord and brain, but there is also remarkable modulation where pain messages are initiated — at the level of the primary sensory neuron. Efforts to determine how these neurons detect pain-producing stimuli of a thermal, mechanical or chemical nature have revealed new signaling mechanisms and brought us closer to understanding the molecular events that facilitate transitions from acute to persistent pain.

biochemistry of pain el paso tx.The Neurochemistry Of Nociceptors

Glutamate is the predominant excitatory neurotransmitter in all nociceptors. Histochemical studies of adult DRG, however, reveal two broad classes of unmyelinated C fiber.

Chemical Transducers To Make The Pain Worse

As described above, injury heightens our pain experience by increasing the sensitivity of nociceptors to both thermal and mechanical stimuli. This phenomenon results, in part, from the production and release of chemical mediators from the primary sensory terminal and from non-neural cells (for example, fibroblasts, mast cells, neutrophils and platelets) in the environment36 (Fig. 3). Some components of the inflammatory soup (for example, protons, ATP, serotonin or lipids) can alter neuronal excitability directly by inter- acting with ion channels on the nociceptor surface, whereas others (for example, bradykinin and NGF) bind to metabotropic receptors and mediate their effects through second-messenger signaling cascades11. Considerable progress has been made in understanding the biochemistry basis of such modulatory mechanisms.

Extracellular Protons & Tissue Acidosis

Local tissue acidosis is a hallmark physiological response to injury, and the degree of associated pain or discomfort is well correlated with the magnitude of acidification37. Application of acid (pH 5) to the skin produces sustained discharges in a third or more of polymodal nociceptors that innervate the receptive field 20.

biochemistry of pain el paso tx.Cellular & Molecular Mechanisms Of Pain

Abstract

The nervous system detects and interprets a wide range of thermal and mechanical stimuli as well as environmental and endogenous chemical irritants. When intense, these stimuli generate acute pain, and in the setting of persistent injury, both peripheral and central nervous system components of the pain transmission pathway exhibit tremendous plasticity, enhancing pain signals and producing hypersensitivity. When plasticity facilitates protective reflexes, it can be beneficial, but when the changes persist, a chronic pain condition may result. Genetic, electrophysiological, and pharmacological studies are elucidating the molecular mechanisms that underlie detection, coding, and modulation of noxious stimuli that generate pain.

Introduction: Acute Versus Persistent Pain

biochemistry of pain el paso tx.

biochemistry of pain el paso tx.Figure 5. Spinal Cord (Central) Sensitization

  1. Glutamate/NMDA receptor-mediated sensitization. Following intense stimulation or persistent injury, activated C and Aδ nociceptors release a variety of neurotransmitters including dlutamate, substance P, calcitonin-gene related peptide (CGRP), and ATP, onto output neurons in lamina I of the superficial dorsal horn (red). As a consequence, normally silent NMDA glutamate receptors located in the postsynaptic neuron can now signal, increase intracellular calcium, and activate a host of calcium dependent signaling pathways and second messengers including mitogen-activated protein kinase (MAPK), protein kinase C (PKC), protein kinase A (PKA) and Src. This cascade of events will increase the excitability of the output neuron and facilitate the transmission of pain messages to the brain.
  2. Disinhibition. Under normal circumstances, inhibitory interneurons (blue) continuously release GABA and/or glycine (Gly) to decrease the excitability of lamina I output neurons and modulate pain transmission (inhibitory tone). However, in the setting of injury, this inhibition can be lost, resulting in hyperalgesia. Additionally, disinhibition can enable non-nociceptive myelinated Aβ primary afferents to engage the pain transmission circuitry such that normally innocuous stimuli are now perceived as painful. This occurs, in part, through the disinhibition of excitatory PKCγ expressing interneurons in inner lamina II.
  3. Microglial activation. Peripheral nerve injury promotes release of ATP and the chemokine fractalkine that will stimulate microglial cells. In particular, activation of purinergic, CX3CR1, and Toll-like receptors on microglia (purple) results in the release of brain-derived neurotrophic factor (BDNF), which through activation of TrkB receptors expressed by lamina I output neurons, promotes increased excitability and enhanced pain in response to both noxious and innocuous stimulation (that is, hyperalgesia and allodynia). Activated microglia also release a host of cytokines, such as tumor necrosis factor α (TNFα), interleukin-1β and 6 (IL-1β, IL-6), and other factors that contribute to central sensitization.

The Chemical Milieu Of Inflammation

Peripheral sensitization more commonly results from inflammation-associated changes in the chemical environment of the nerve fiber (McMahon et al., 2008). Thus, tissue damage is often accompanied by the accumulation of endogenous factors released from activated nociceptors or non-neural cells that reside within or infiltrate into the injured area (including mast cells, basophils, platelets, macrophages, neutrophils, endothelial cells, keratinocytes, and fibroblasts). Collectively. these factors, referred to as the ‘inflammatory soup’, represent a wide array of signaling molecules, including neurotransmitters, peptides (substance P, CGRP, bradykinin), eicosinoids and related lipids (prostaglandins, thromboxanes, leukotrienes, endocannabinoids), neurotrophins, cytokines, and chemokines, as well as extracellular proteases and protons. Remarkably, nociceptors express one or more cell surface receptors capable of recognizing and responding to each of these pro-inflammatory or pro-algesic agents (Figure 4). Such interactions enhance excitability of the nerve fiber, thereby heightening its sensitivity to temperature or touch.

Unquestionably the most common approach to reducing inflammatory pain involves inhibiting the synthesis or accumulation of components of the inflammatory soup. This is best exemplified by non-steroidal anti-inflammatory drugs, such as aspirin or ibuprofen, which reduce inflammatory pain and hyperalgesia by inhibiting cyclooxygenases (Cox-1 and Cox-2) involved in prostaglandin synthesis. A second approach is to block the actions of inflammatory agents at the nociceptor. Here, we highlight examples that provide new insight into cellular mechanisms of peripheral sensitization, or which form the basis of new therapeutic strategies for treating inflammatory pain.

NGF is perhaps best known for its role as a neurotrophic factor required for survival and development of sensory neurons during embryogenesis, but in the adult, NGF is also produced in the setting of tissue injury and constitutes an important component of the inflammatory soup (Ritner et al., 2009). Among its many cellular targets, NGF acts directly on peptidergic C fiber nociceptors, which express the high affinity NGF receptor tyrosine kinase, TrkA, as well as the low affinity neurotrophin receptor, p75 (Chao, 2003; Snider and McMahon, 1998). NGF produces profound hypersensitivity to heat and mechanical stimuli through two temporally distinct mechanisms. At first, a NGF-TrkA interaction activates downstream signaling pathways, including phospholipase C (PLC), mitogen-activated protein kinase (MAPK), and phosphoinositide 3-kinase (PI3K). This results in functional potentiation of target proteins at the peripheral nociceptor terminal, most notably TRPV1, leading to a rapid change in cellular and behavioral heat sensitivity (Chuang et al., 2001).