Spontaneous Trigeminal Allodynia in Rats: A Model of Primary Headache

Headache: The Journal of Head and Face Pain

1. M.L. Oshinsky PhD^*, 
2. M.M. Sanghvi MS, 
3. C.R. Maxwell PhD, 
4. D. Gonzalez MS, 
5. R.J. Spangenberg MLAS, 
6. M. Cooper BS, 
7. S.D. Silberstein MD

1.  michael.oshinsky@jefferson.edu

DOI: 10.1111/j.1526-4610.2012.02247.x

Abstract

Animal models are essential for studying the pathophysiology of headache disorders and as a screening tool for new therapies. Most animal models modify a normal animal in an attempt to mimic migraine symptoms. They require manipulation to activate the trigeminal nerve or dural nociceptors. At best, they are models of secondary headache. No existing model can address the fundamental question: How is a primary headache spontaneously initiated?

In the process of obtaining baseline periorbital von Frey thresholds in a wild-type Sprague-Dawley rat, we discovered a rat with spontaneous episodic trigeminal allodynia (manifested by episodically changing low periorbital pain threshold). Subsequent mating showed that the trait is inherited. Animals with spontaneous trigeminal allodynia allow us to study the pathophysiology of primary recurrent headache disorders.

To validate this as a model for migraine, we tested the effects of clinically proven acute and preventive migraine treatments on spontaneous changes in rat periorbital sensitivity. Sumatriptan, ketorolac, and dihydroergotamine temporarily reversed the low periorbital pain thresholds. Thirty days of chronic valproic acid treatment prevented spontaneous changes in trigeminal allodynia. After discontinuation, the rats returned to their baseline of spontaneous episodic threshold changes. We also tested the effects of known chemical and dietary human migraine triggers. On days when the rats did not have allodynia and showed normal periorbital von Frey thresholds, glycerol trinitrate and calcitonin gene related peptide induced significant decreases in the periorbital pain threshold.

This model can be used as a predictive model for drug development and for studies of putative biomarkers for headache diagnosis and treatment.

© 2012 American Headache Society

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.

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
Research Submission
Allodynia in Migraine: Association With Comorbid Pain Conditions
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

Copyright Copyright © 2009 American Headache Society

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.


--------------------------------------------------------------------------------

Reduction of allodynia in patients with complex regional pain syndrome: A double-blind placebo-controlled trial of topical ketamine

Reduction of allodynia in patients with complex regional pain syndrome: A double-blind placebo-controlled trial of topical ketamine
(http://www.painjournalonline.com/article/PIIS0304395909003042/abstract?)
Philip M. Finchab, Lone Knudsenb, Peter D. Drummondb
Received 4 February 2009; received in revised form 22 April 2009; accepted 19 May 2009. published online 25 August 2009. Corrected Proof
Abstract
A double-blind placebo-controlled crossover trial was used to determine the effects of topical ketamine, an N-methyl-d-aspartate (NMDA) receptor antagonist, on the sensory disturbances in 20 patients with complex regional pain syndrome (CRPS). On two occasions separated by at least one week, sensory tests to light touch, pressure, punctate stimulation, light brushing and thermal stimuli were performed in the symptomatic and contralateral limb and on each side of the forehead before and 30min after 10% ketamine cream was applied to the symptomatic or healthy limb. Venous blood for the plasma estimations of ketamine and norketamine was obtained 1h after application of the creams. Ketamine applied to the symptomatic limb inhibited allodynia to light brushing and hyperalgesia to punctate stimulation. Systemic effects of the ketamine are unlikely to account for this as the plasma levels were below detectable limits. As touch thresholds were unchanged, NMDA receptors may contribute to the sensory disturbances in CRPS via actions at cutaneous nociceptors. Allodynia and hyperalgesia were detected in the ipsilateral forehead to a range of stimuli (brushing, pressure, punctate stimulation, cold, heat, and warmth). In several patients, ketamine treatment of the symptomatic limb inhibited allodynia to brushing the ipsilateral forehead, suggesting that the mechanism that mediates allodynia in the symptomatic limb contributed to allodynia at more remote sites. The present study shows promise for the use of topical ketamine as opposed to parenteral and oral forms which often result in undesirable side effects.