Chronic stress induces transient spinal neuroinflammation, triggering sensory hypersensitivity and long-lasting anxiety-induced hyperalgesia

PAIN

Cyril Rivatabc, Chrystel Beckerabce, Aurélie Blugeotabc, Brigitte Zeauabc, Annie Mauborgneabc, Michel Pohlabc, Jean-Jacques Benolielabcd

Received 18 January 2010; received in revised form 28 May 2010; accepted 28 May 2010. published online 24 June 2010.

Abstract

Chronic stressful events induce biochemical, physiological and psychological changes, resulting in stress-related neuropsychiatric disorders, such as anxiety or depression. Using repeated social defeat as a stressful event model, we show that this preclinical paradigm induces a transient increase in the expression of the genes encoding the pro-inflammatory molecules iNOS and COX-2. We provide the first demonstration that chronic stress affects spinal plasticity through a mechanism involving local neuroinflammation. The functional consequences of such neuroinflammation are associated with a transient decrease in the mechanical nociceptive threshold. Administration of the cholecystokinin(CCK)-2 receptor antagonist, CI-988, directly into the Rostral Ventromedial Medulla reverses the chronic stress-induced decrease in the nociceptive threshold.

These data strongly suggest that chronic stress induces a spinal neuroinflammation associated with transient sensory hypersensitivity involving the activation of CCK-dependent nociceptive descending facilitatory pathways. Pharmacological data show that chronic social stress-induced long-lasting state of anxiety is not responsible for maintaining the spinal neuroinflammation and, therefore, for the associated sensory hypersensitivity. Conversely, an evaluation of pain-related behavior in the formalin model indicates that anxiety is directly related to prolonged hyperalgesia prevented by systemic benzodiazepine or CCK-2 receptor antagonist treatments. The present study highlights the adverse effects of chronic stress on spinal neuroinflammation triggering sensory hypersensitivity. Exploration of this phenomenon points out the divergence between pain sensitivity and anxiety-induced hyperalgesia, which is in agreement with clinical observations. Altogether, these data open up new perspectives for clinical research devoted to the evaluation and treatment of pain in anxio-depressive patients.

Corresponding author. Address: Université Pierre et Marie Curie-Paris 6, UMRS 975, PAIN team, Paris 75013, France. Tel.: +33 1 4077 8172; fax: +33 1 4077 9645

Chronic Headaches and the Neurobiology of Somatization

 Current Pain and Headache Reports
Jonathan M. Borkum (Department of Psychology, University of Maine and Health Psych Maine, 2 Big Sky Lane, Waterville, ME 04901, USA)

Published online: 15 January 2010

Abstract Pain sensitivity is an adaptive process affected by expectation, mood, coping, operant conditioning, and the preconscious allocation of attention. Underlying mechanisms may include encoding of similar experiences (eg, depression, loss, pain-distress) in overlapping patterns of activation, failure of common regulatory mechanisms, direct top-down activation of the pain matrix, and changes in descending pain facilitatory and inhibitory tone. In theory, the combination of glial cell activation from psychological stress and neural firing from nociceptive input may be particularly likely to lead to pain sensitization and long-term structural changes in pain processing regions of the brain. In these ways, headaches in which chronicity, diffuseness, and distress seem better accounted for by psychological than by medical variables can be understood in neurobiological terms. This can allow psychological treatment of physical distress to be objective, nonthreatening, and relatively precise.

Allodynia in Migraine: Association With Comorbid Pain Conditions

Headache: The Journal of Head and Face Pain
Volume 49 Issue 9, Pages 1333 - 1344
Published Online: 29 Sep 2009
Copyright © 2009 American Headache Society

Gretchen E. Tietjen, MD; Jan L. Brandes, MD; B. Lee Peterlin, DO; Arnolda Eloff, MD; Rima M. Dafer, MD, MPH; Michael R. Stein, MD; Ellen Drexler, MD; Vincent T. Martin, MD; Susan Hutchinson, MD; Sheena K. Aurora, MD; Ana Recober, MD; Nabeel A. Herial, MD, MPH; Christine Utley, MSN, CNP; Leah White, MPH; Sadik A. Khuder, MPH, PhD
From The University of Toledo College of Medicine, Toledo, OH, USA (G.E. Tietjen, N.A. Herial, C. Utley, L. White, and S.A. Khuder); Nashville Neuroscience Group, Nashville, TN, USA (J.L. Brandes); Drexel University College of Medicine, Philadelphia, PA, USA (B.L. Peterlin); University of Calgary, Calgary, AB, Canada (A. Eloff); Loyola University Medical Center, Maywood, IL, USA (R.M. Dafer); John Muir Medical Center, Walnut Creek, CA, USA (M.R. Stein); Maimonides Medical Center, Brooklyn, NY, USA (E. Drexler); University of Cincinnati, Cincinnati, OH, USA (V.T. Martin); Orange County Migraine & Headache Center, Irvine, CA, USA (S. Hutchinson); Swedish Headache Center, Seattle, WA, USA (S.K. Aurora); University of Iowa, Iowa City, IA, USA (A. Recober).
Correspondence to G.E. Tietjen, 3000 Arlington Avenue, Mailstop 1195, Department of Neurology, The University of Toledo College of Medicine, Toledo, OH 43614, USA.
Financial support: This work was in part supported with a section grant from the American Headache Society.

Conflict of Interest: None

ABSTRACT
Background.—Cutaneous allodynia (CA) in migraine is a clinical manifestation of central nervous system sensitization. Several chronic pain syndromes and mood disorders are comorbid with migraine. In this study we examine the relationship of migraine-associated CA with these comorbid conditions. We also evaluate the association of CA with factors such as demographic profiles, migraine characteristics, and smoking status that may have an influence on the relationships of CA to pain and mood.

Methods.—Data are from a cross-sectional multicenter study of comorbid conditions in persons seeking treatment in headache clinics. Diagnosis of migraine was determined by a physician based on the International Classification of Headache Disorders-II criteria. Participants completed a self-administered questionnaire ascertaining sociodemographics, migraine-associated allodynia, physician-diagnosed comorbid medical and psychiatric disorders, headache-related disability, current depression, and anxiety.

Results.—A total of 1413 migraineurs (mean age = 42 years, 89% women) from 11 different headache treatment centers completed a survey on the prevalence of comorbid conditions. Aura was reported by 38% and chronic headache by 35% of the participants. Sixty percent of the study population reported at least one migraine-related allodynic symptom, 10% reported ≥4 symptoms. Symptoms of CA were associated with female gender, body mass index, current smoking, presence of aura, chronic headaches, transformed headaches, severe headache-related disability, and duration of migraine illness from onset. The prevalence of self-reported physician diagnosis of comorbid pain conditions (irritable bowel syndrome, chronic fatigue syndrome, fibromyalgia) and psychiatric conditions (current depression and anxiety) was also associated with symptoms of CA. Adjusted ordinal regression indicated a significant association between number of pain conditions and severity of CA (based on symptom count). Adjusting for sociodemographics, migraine characteristics, and current depression and anxiety, the likelihood of reporting symptoms of severe allodynia was much higher in those with 3 or more pain conditions (odds ratio = 3.03, 95% confidence interval: 1.78-5.17), and 2 pain conditions (odds ratio = 2.67, 95% confidence interval: 1.78-4.01) when compared with those with no comorbid pain condition.

Conclusion.—Symptoms of CA in migraine were associated with current anxiety, depression, and several chronic pain conditions. A graded relationship was observed between number of allodynic symptoms and the number of pain conditions, even after adjusting for confounding factors. This study also presents the novel association of CA symptoms with younger age of migraine onset, and with cigarette smoking, in addition to confirming several previously reported findings.

The coexistence of neuropathic pain, sleep, and psychiatric disorders: a novel treatment approach.

,Argoff CE.
Cohn Pain Management Center, North Shore-LIJ Health System, NY, USA. pargoff@optonline.net

The diagnosis and treatment of neuropathic pain may be complicated by comorbid conditions such as sleep disturbances, depression, and anxiety. The interrelationship between the index neuropathic pain state and these comorbidities is complex: comorbid conditions exacerbate pain, and in turn, pain exacerbates the comorbid conditions. Because comorbidities can negatively impact response to pain treatment, healthcare providers should assess comorbidities as part of the diagnostic work-up, and management strategies should be designed to treat the whole patient, not just the pain. Theoretically, therapies that not only reduce pain, but also improve sleep and reduce anxiety and depression can provide multiple benefits without the risk of increased side effects inherent in combination therapy. Anticonvulsants and antidepressants have demonstrated efficacy in improving neuropathic pain and positively impacting comorbid sleep and mood disturbances. Novel anticonvulsants that can address one or more comorbidities in addition to pain may represent viable treatment options for patients with neuropathic pain.

PMID: 17277640 [PubMed - indexed for MEDLINE]

Depression and anxiety associated with three pain conditions: results from a nationally representative sample.

Pain. 2004 Sep;111(1-2):77-83.

McWilliams LA, Goodwin RD, Cox BJ.

Department of Psychology, PZ-430 PsycHealth Centre, University of Manitoba, 771 Bannatyne Avenue, Winnipeg, Man. R3E 3N4, Canada. UMMCWIL1@cc.umanitoba.ca

Investigations of the relationship between pain conditions and psychopathology have largely focused on depression and have been limited by the use of non-representative samples (e.g. clinical samples). The present study utilized data from the Midlife Development in the United States Survey (MIDUS) to investigate associations between three pain conditions and three common psychiatric disorders in a large sample (N = 3,032) representative of adults aged 25-74 in the United States population. MIDUS participants provided reports regarding medical conditions experienced over the past year including arthritis, migraine, and back pain. Participants also completed several diagnostic-specific measures from the Composite International Diagnostic Interview-Short Form [Int. J. Methods Psychiatr. Res. 7 (1998) 171], which was based on the revised third edition of the Diagnostic and Statistical Manual of Mental Disorders [American Psychiatric Association 1987]. The diagnoses included were depression, panic attacks, and generalized anxiety disorder. Logistic regression analyses revealed significant positive associations between each pain condition and the psychiatric disorders (Odds Ratios ranged from 1.48 to 3.86). The majority of these associations remained statistically significant after adjusting for demographic variables, the other pain conditions, and other medical conditions. Given the emphasis on depression in the pain literature, it was noteworthy that the associations between the pain conditions and the anxiety disorders were generally larger than those between the pain conditions and depression. These findings add to a growing body of evidence indicating that anxiety disorders warrant further attention in relation to pain. The clinical and research implications of these findings are discussed.

Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

PMID: 15327811 [PubMed - indexed for MEDLINE]