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The Biology of Serotonin Receptors: Focus on Migraine Pathophysiology and Treatment

Published online by Cambridge University Press:  02 December 2014

Edith Hamel
Edith Hamel*
Affiliation:
Montreal Neurological Institute, McGill University, Montreal, QC, Canada
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Abstract

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Serotonin receptors are highly heterogeneous and they have been regrouped within seven different families (5-HT1 - 5-HT7). With the exception of the 5-HT3 which is a ligand-gated ion channel, all others are G-protein coupled receptors with each family sharing structural, pharmacological and transductional characteristics. 5-HT receptors have been implicated in the regulation of several psychiatric and neurological disorders related to serotonergic neurotransmission, and specific receptor subtypes have recently been associated with either the pathogenesis or the treatment of migraine headache. In this respect, activation of vascular 5-HT2B and/or 5-HT7 receptors, possibly as a consequence of the sudden rise in 5-HT levels reported at the onset of a migraine attack, would hypothetically result in dilation of cerebral blood vessels and concomitant activation of sensory trigeminovascular afferents, hence initiating the manifestation of head pain. At this stage in the migraine process, activation of specific subtypes of 5-HT1 receptors has proven clinically effective in relieving migraine pain. Neural 5-HT1D and/or 5-HT1F receptors localized pre-junctionally on trigeminovascular afferents appear to mediate the triptan-induced inhibition of the neurogenic inflammatory response, with possible additional sites of action for brain penetrant 5-HT1 receptor agonists in inhibiting the transmission of pain centrally. In contrast, activation of vascular 5-HT1B receptors would constrict meningeal vessels hence recovering their pre-migraine diameter. The recent availability of subtype selective 5-HT1D and 5-HT1F receptor agonists should allow a further test of the neural/vascular hypothesis and could possibly lead to antimigraine drugs with a safer cardiovascular profile.

Résumé

RÉSUMÉ

On les a regroupés en 7 familles différentes (5-HT1 – 5-HT7). À l’exception de 5HT3 qui appartient à la famille des récepteurs canaux, tous les autres appartiennent à la famille des récepteurs couplés à la protéine G et chaque famille a des caractéristiques structurales, pharmacologiques et transductionnelles communes. Les récepteurs 5-HT ont été impliqués dans la régulation de plusieurs maladies psychiatriques et neurologiques reliées à la neurotransmission sérotoninergique et des sous-types de récepteurs spécifiques ont été associés récemment à la pathogenèse ou au traitement de la migraine. À ce sujet, l’activation de récepteurs vasculaires 5-HT2b et/ou 5-HT7, possiblement comme conséquence de la hausse soudaine des niveaux de 5-HT rapportés au début d’un accès de migraine, provoquerait hypothétiquement une dilatation des vaisseaux sanguins cérébraux et une activation concomitante des afférents trigéminovasculaires sensitifs, amorçant ainsi la manifestation de la céphalée. À ce stage dans le processus migraineux, l’efficacité de l’activation de sous-types spécifiques de récepteurs 5-HT1 pour soulager la douleur migraineuse a été démontrée en clinique. Les récepteurs neuronaux 5-HT1D et/ou 5-HT1F localisés en présynapse sur les afférents trigéminovasculaires semblent médier l’inhibition de la réponse inflammatoire neurogène induite par le triptan. Il est également possible qu’il existe des sites additionnels pour les agonistes des récepteurs 5-HT1 qui pénètrent dans le cerveau et qui inhibent la transmission centrale de la douleur. Par ailleurs, l’activation des récepteurs vasculaires 5-HT1B provoquerait une vasoconstriction des vaisseaux méningés qui reprendraient ainsi leur diamètre pré-migraine. L’arrivée d’agonistes sélectifs pour les sous-types de récepteurs 5-HT1D et 5-HT 1F devrait permettre de tester l’hypothèse nerveuse/vasculaire et pourrait peut-être mener au développement de médicaments antimigraineux ayant un profil cardiovasculaire plus sûr.

Type
Research Article
Information
Canadian Journal of Neurological Sciences , Volume 26 , Issue 3 , November 1999 , pp. 2 - 6
Copyright
Copyright © The Canadian Journal of Neurological 1999

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