Medical Hypotheses
Volume 73, Issue 5, Pages 633-866 (November 2009)
Ambar Chakravarty, Department of Neurology, Vivekananda Institute of Medical Science, 1E 1202, Avishikta II, Calcutta 700 078, India (Tel.: +91 33 24843283.)
Summary
A trigger is an integral part of any acute migraine attack. In this article, the author argues that triggers, identifiable or not, must be present in all attacks of migraine headache. It is hypothesized that triggers, internal or external, induce the onset of cortical spreading depression (CSD) in a pre-existing hyper-excitable cortex of a migraine brain, initiating the process of pain generation.
The author hypothesizes on a second site of action of triggers at the level of trigeminal nuclear complex (TNC) in brain stem, the cell station of second order neuron pathway for migraine pain transmission to the sensory cortex.
The author suggests existence of a hypothetical ‘gate’ at TNC level where incoming trigeminal migraine pain impulses would ‘compete’ with descending inhibitory signals from brain stem pain modulatory neurons, to get entry into the central nervous system. The author draws analogy with the ‘gate control’ mechanism operative at the dorsal horn level for spinally transmitted somatic and visceral pain. It is suggested that the hypothetical ‘gate’ at TNC level is controlled by activity of 5HT receptors, thus supporting the concept of an additional site of action of triptans in aborting acute migraine pain.
The suggested hypothesis on mechanism of action of triggers, offers theoretical basis for efficacy of currently available pharmacologic and non-pharmacologic therapies for abortive and prophylactic treatment of migraine.
Showing posts with label cortical spreading depression. Show all posts
Showing posts with label cortical spreading depression. Show all posts
Wednesday, November 25, 2009
Friday, October 30, 2009
Separating headache from aura
Cortical spreading depression (CSD) is a phenomenon characterized by a slowly spreading depolarization of cortical cells and is postulated to cause aura associated with migraine. Recently drugs that block gap junctions have been developed to inhibit CSD. In this paper the authors tested the effect of one such drug, tonabersat in patients with migraine. They examined 39 patients in a double blind crossover study and measured attacks of aura with or without headache and migraine headache days with or without aura as primary outcomes. The results showed that tonabersat reduced the number of aura attacks and attacks of aura followed by headache but not the number of migraine headache days. These results suggest that migraine with aura and migraine without aura involve different pathophysiological mechanisms. The study also suggests that drugs targeting gap junctions may be effective in treating migraine with aura (Lancet Neurol 2009 8:718-723).
Tuesday, October 13, 2009
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.
--------------------------------------------------------------------------------
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.
--------------------------------------------------------------------------------
Monday, September 21, 2009
Neurological mechanisms of migraine: potential of the gap-junction modulator tonabersat in prevention of migraine.
Durham PL, Garrett FG.
Center for Biomedical and Life Sciences, Missouri State University, Springfield, MO 65897, USA. pauldurham@missouristate.edu
Migraine is a neurovascular disorder characterized by recurrent episodic headaches, and is caused by abnormal processing of sensory information due to peripheral and/or central sensitization. The exact pathophysiological mechanism underlying migraine is not fully understood; however, cortical spreading depression (CSD) is thought to provide the basis for migraine aura and may serve as a trigger of migraine pain. CSD depends on neuronal-glial cell communication, which is mediated by intercellular transfer of messengers through connexin-containing gap junctions, as well as messengers released into the extracellular space by non-junctional connexin-containing hemichannels. These processes are believed to be important in peripheral sensitization within the trigeminal ganglion and to lead to central sensitization. The novel benzopyran compound tonabersat binds selectively to a unique site in the brain. In preclinical studies, tonabersat markedly reduced CSD and CSD-associated events and inhibited gap-junction communication between neurons and satellite glial cells in the trigeminal ganglion. Together, these findings suggest that tonabersat should have clinical application in preventing migraine attacks.
Cephalalgia. 2009 Nov;29 Suppl 2:1-6
Center for Biomedical and Life Sciences, Missouri State University, Springfield, MO 65897, USA. pauldurham@missouristate.edu
Migraine is a neurovascular disorder characterized by recurrent episodic headaches, and is caused by abnormal processing of sensory information due to peripheral and/or central sensitization. The exact pathophysiological mechanism underlying migraine is not fully understood; however, cortical spreading depression (CSD) is thought to provide the basis for migraine aura and may serve as a trigger of migraine pain. CSD depends on neuronal-glial cell communication, which is mediated by intercellular transfer of messengers through connexin-containing gap junctions, as well as messengers released into the extracellular space by non-junctional connexin-containing hemichannels. These processes are believed to be important in peripheral sensitization within the trigeminal ganglion and to lead to central sensitization. The novel benzopyran compound tonabersat binds selectively to a unique site in the brain. In preclinical studies, tonabersat markedly reduced CSD and CSD-associated events and inhibited gap-junction communication between neurons and satellite glial cells in the trigeminal ganglion. Together, these findings suggest that tonabersat should have clinical application in preventing migraine attacks.
Cephalalgia. 2009 Nov;29 Suppl 2:1-6
Tonabersat, a novel gap-junction modulator for the prevention of migraine.
Silberstein SD.
Jefferson Headache Center, Philadelphia, PA 19107, USA. stephen.silberstein@jefferson.edu
Migraine is a common, recurrent, primary headache disorder associated with significant morbidity as well as high direct and indirect costs. Despite its impact, only a proportion of migraineurs who meet criteria for prophylactic treatment take preventive medication. Antiepileptic drugs and beta-blockers are among the most used preventive therapies, but their exact mechanisms of action in migraine prophylaxis are unknown. Recent research has pointed to the role of cortical spreading depression in the genesis of migraine aura and pain, with neuronal-glial gap junctions playing a prominent part in cortical spreading depression. Tonabersat is a unique compound with demonstrated activity as a gap-junction inhibitor in animal studies. In preclinical and clinical trials, tonabersat was well tolerated, with no cardiovascular effects; the pharmacokinetic profile suggested its usefulness in the prophylaxis of migraine.
Cephalalgia. 2009 Nov;29 Suppl 2:28-35.
Jefferson Headache Center, Philadelphia, PA 19107, USA. stephen.silberstein@jefferson.edu
Migraine is a common, recurrent, primary headache disorder associated with significant morbidity as well as high direct and indirect costs. Despite its impact, only a proportion of migraineurs who meet criteria for prophylactic treatment take preventive medication. Antiepileptic drugs and beta-blockers are among the most used preventive therapies, but their exact mechanisms of action in migraine prophylaxis are unknown. Recent research has pointed to the role of cortical spreading depression in the genesis of migraine aura and pain, with neuronal-glial gap junctions playing a prominent part in cortical spreading depression. Tonabersat is a unique compound with demonstrated activity as a gap-junction inhibitor in animal studies. In preclinical and clinical trials, tonabersat was well tolerated, with no cardiovascular effects; the pharmacokinetic profile suggested its usefulness in the prophylaxis of migraine.
Cephalalgia. 2009 Nov;29 Suppl 2:28-35.
Friday, September 4, 2009
The Mode of Action of Migraine Triggers: A Hypotheis
Lambert and Zagami has written a review article in "Headache" Feb 2009 edition.
It is on "The Mode of Action of Migraine Triggers: A Hypotheis"And the abstract says: Pain of migraine originates in the cortex, the immediate generator is in the brainstem.
Normally there is a descending sensory inhibition from the brainstem. Triggers in most migraines produce excitation of cortical neurons. This causes withdrawal of descending sensory inhibition that originate in the brainstem.
Many brainstem nuclei seem to participate in the selective control of trigeminovascular sensation. This is through descending inhibitory mechanisms arising in the cortex. Peri-Aquiductal Gray matter and Nucleus Raphe Magnus are important here. Neurotransmitter 5-hydroxytryptamine is involved.
They summarize that cortical activation by migraine triggers (including cortical spreading depression) inhibits neuronal discharge in the brainstem. This facilitates trigeminovascular sensation.
Headache. 49(2):253-275, February 2009.Lambert, Geoffrey A. PhD; Zagami, Alessandro S. MBBS, MD
It is on "The Mode of Action of Migraine Triggers: A Hypotheis"And the abstract says: Pain of migraine originates in the cortex, the immediate generator is in the brainstem.
Cortical activation induced by many different mechanisms often produce headache.
Normally there is a descending sensory inhibition from the brainstem. Triggers in most migraines produce excitation of cortical neurons. This causes withdrawal of descending sensory inhibition that originate in the brainstem.
Many brainstem nuclei seem to participate in the selective control of trigeminovascular sensation. This is through descending inhibitory mechanisms arising in the cortex. Peri-Aquiductal Gray matter and Nucleus Raphe Magnus are important here. Neurotransmitter 5-hydroxytryptamine is involved.
They summarize that cortical activation by migraine triggers (including cortical spreading depression) inhibits neuronal discharge in the brainstem. This facilitates trigeminovascular sensation.
Headache. 49(2):253-275, February 2009.Lambert, Geoffrey A. PhD; Zagami, Alessandro S. MBBS, MD
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