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Pathophysiology of Migraine — New Insights

Published online by Cambridge University Press:  02 December 2014

RJ Hargreaves  and
SL Shepheard
RJ Hargreaves
Affiliation:
Merck Research Laboratories, West Point PA USA
SL Shepheard
Affiliation:
Merck Research Laboratories, West Point PA USA Merck Sharp and Dohme, Neuroscience Research Centre, Harlow, Essex, UK
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Abstract

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Current theories propose that the primary dysfunction in migraine occurs within the CNS and that this evokes changes in blood vessels within pain-producing intracranial meningeal structures that give rise to headache pain. Migraine is now thought of as a neurovascular disorder. It has been proposed that genetic abnormalities may be responsible for altering the response threshold to migraine specific trigger factors in the brain of a migraineur compared to a normal individual. The exact nature of the central dysfunction that is produced in migraineurs is still not clear and may involve spreading depression-like phenomena and activation of brain stem monoaminergic nuclei that are part of the central autonomic, vascular and pain control centers. It is generally thought that local vasodilatation of intracranial extracerebral blood vessels and a consequent stimulation of surrounding trigeminal sensory nervous pain pathways is a key mechanism underlying the generation of headache pain associated with migraine. This activation of the ‘trigeminovascular system’ is thought to cause the release of vasoactive sensory neuropeptides, especially CGRP, that increase the pain response. The activated trigeminal nerves convey nociceptive information to central neurons in the brain stem trigeminal sensory nuclei that in turn relay the pain signals to higher centers where headache pain is perceived. It has been hypothesized that these central neurons may become sensitized as a migraine attack progresses. The ‘triptan’ anti-migraine agents (e.g. sumatriptan, rizatriptan, zolmitriptan naratriptan) are serotonergic agonists that have been shown to act selectively by causing vasoconstriction through 5-HT1B receptors that are expressed in human intracranial arteries and by inhibiting nociceptive transmission through an action at 5-HT1D receptors on peripheral trigeminal sensory nerve terminals in the meninges and central terminals in brain stem sensory nuclei. These three complementary sites of action underlie the clinical effectiveness of the 5-HT1B/1D agonists against migraine headache pain and its associated symptoms.

Résumé

RÉSUMÉ

Les théories actuelles proposent que la dysfonction primaire dans la migraine est localisée dans le SNC et qu’elle provoque des changements dans les vaisseaux sanguins localisés dans les structures méningées intracrâniennes produisant ainsi la douleur. La céphalée résulte de ces changements. On pense maintenant que la migraine est un désordre neurovasculaire. Des anomalies génétiques pourraient être responsables de l’altération du seuil de la réponse aux facteurs spécifiques déclenchant la migraine dans le cerveau d’un migraineux comparé à un individu normal. La nature exacte de la dysfonction centrale chez les migraineux n’est pas encore claire et pourrait impliquer un phénomène qui se propage ressemblant à la dépression et à l’activation des noyaux monoaminergiques du tronc cérébral qui font partie des centres autonomes, vasculaires et du contrôle de la douleur. On pense en général que la vasodilatation locale des vaisseaux sanguins intracrâniens extracérébraux et une stimulation des voies sensitives nociceptives adjacentes du trijumeau constituent un mécanisme clé dans la production de la céphalée associée à la migraine. On pense que cette activation du “système trigéminovasculaire” provoque la libération de neuropeptides sensitifs vasoactifs, spécialement du CGRP qui augmente la réponse douloureuse. Les nerfs trijumeaux activés amènent l’information nociceptive aux neurones centraux situés dans les noyaux sensitifs trigéminés du tronc cérébral qui, à leur tour, relayent les signaux douloureux aux centres supérieurs où la douleur est perçue. On a émis l’hypothèse que ces neurones centraux peuvent devenir sensibilisés à mesure que l’accès de migraine progresse. Les agents antimigraineux de la famille du triptan (sumatriptan, rizatriptan, zolmitriptan, naratriptan) sont des agonistes sérotoninergiques dont l’action sélective sur les récepteurs 5-HT1B, exprimés dans les artères intracrâniennes humaines, cause une vasoconstriction et inhibe la transmission nociceptive par leur action sur les récepteurs 5-HT1D situés sur les terminaisons nerveuses sensitives périphériques du trijumeau dans les méninges et sur les terminaisons centrales dans les noyaux sensitifs du tronc cérébral. Ces trois sites complémentaires d’activité expliquent l’efficacité clinique des agonistes 5-HT1B/1D contre la migraine et ses symptômes associés.

Type
Research Article
Information
Canadian Journal of Neurological Sciences , Volume 26 , Issue 3 , November 1999 , pp. 12 - 19
Copyright
Copyright © The Canadian Journal of Neurological 1999

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