Hostname: page-component-78c5997874-fbnjt Total loading time: 0 Render date: 2024-11-10T07:51:52.122Z Has data issue: false hasContentIssue false
  • English
  • Français

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
Rights & Permissions [Opens in a new window]

Abstract

Core share and HTML view are not available for this content. However, as you have access to this content, a full PDF is available via the ‘Save PDF’ action button.

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

References

1. Martin, GR, Humphrey, PPA. Receptors for 5-hydroxytryptamine: current perspectives on classification and nomenclature. Neuropharmacology 1994; 33: 261–273.CrossRefGoogle Scholar
2. Pandey, SC, Davis, JM, Pandey, GN. Phosphoinositide system-linked serotonin receptor subtypes and their pharmacological properties and clinical correlates. J Psychiatry Neurosci 1995; 20: 215–225.Google Scholar
3. Gerhardt, CC, van Heerikhuizen, H. Functional characteristics of heterologously expressed 5-HT receptors. Eur J Pharmacol 1997; 334: 1–23.Google Scholar
4. Martin, GR. Serotonin receptor involvement in the pathogenesis and treatment of migraine. In: Silberstein, S, Goadsby, PJ, eds. Headache Blue Books of Practical Neurology, Volume 17, Chapter 2. Butterworth-Heineman, 1997; 25–38.Google Scholar
5. Hoyer, D, Martin, G. 5-HTreceptor classification and nomenclature: towards a harmonization with the human genome. Neuropharmacology 1997; 36: 419–428.Google Scholar
6. Zgombick, JM, Schechter, LE, Kucharewicz, SA, Weinshank, RLand Bracnchek, TA. Ketanserin and ritanserin discriminate between recombinant human 5-HT1Dα and 5-HT1Dβ receptor subtypes. Eur J Pharmacol 1995; 291:9–15.CrossRefGoogle Scholar
7. Phebus, LA, Johnson, KW, Zgombick, JM, et al. Characterization of LY344864 as a pharmacological tool to study 5-HT1F receptors: binding affinities, brain penetration and activity in the neurogenic dural inflammation model of migraine. Life Sci 1997; 61: 2117–2126.Google Scholar
8. Davies, PA, Pistis, M, Hanna, MC, Peters, JA, Lambert, JJ, Hales, TG, and Kirkness, EF. The 5-HT3B subunit is a major determinant of serotonin-receptor function. Nature 1999; 397:359–363.Google Scholar
9. Dahlöf, CGH, Hargreaves, RJ. Pathophysiology and pharmacology of migraine. Is there a place for antiemetics in future treatment strategies? Cephalalgia 1998; 18: 593–604.Google Scholar
10. Bockaert, J, Fozard, JR, Dumuis, A, Clarke, DE. The 5-HT4 receptor: a place in the sun. Trends Pharmacol Sci 1992; 13: 141–145.Google Scholar
11. Eglen, RM, Jasper, JR, Chang, DJ, Martin, GR. The 5-HT7 receptor: orphan found. Trends Pharmacol Sci 1997; 18:104–107.CrossRefGoogle Scholar
12. Terron, JA. The 5-HT7 receptor: a target for novel therapeutic avenues? Drugs 1998; 1: 302–310.Google Scholar
13. Terron, JA. Involvement of the 5-HT7 receptor in cerebrovascular vasodilation: potential impact in migraine. Proc West Pharmacol Soc 1998; 41: 247–251.Google Scholar
14. Moskowitz, MA. Neurogenic versus vascular mechanisms of sumatriptan and ergot alkaloids in migraine. Trends Pharmacol Sci 1992; 13: 307–311.Google Scholar
15. Storer, RJ, Goadsby, PJ. Microiontophoretic application of serotonin (5HT)1B/1D agonists inhibits trigeminal cell firing in the cat. Brain 1997; 120: 2171–2177.Google Scholar
16. Goadsby, PJ. Is a central action of acute antimigraine drugs essential? Cephalalgia 1997; 17(Suppl): 10–11.Google Scholar
17. Fozard, JR. The pharmacological basis of migraine treatment. In: Blau, JN, ed. Migraine: Clinical and Research Aspects, Chapter 10. Baltimore: The Johns Hopkins University Press, 1987; 165–184.Google Scholar
18. Goadsby, PJ, Edvinsson, L. The trigeminovascular system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Ann Neurol 1993; 33: 48–56.Google Scholar
19. Hamel, E, Fan, E, Linville, D, et al. Expression of mRNA for the serotonin 5-hydroxytryptamine1Dβ receptor subtype in human and bovine cerebral arteries. Mol Pharmacol 1993; 44: 242–246.Google ScholarPubMed
20. Bouchelet, I, Cohen, Z, Case, B, Séguéla, P, Hamel, E. Differential expression of sumatriptan-sensitive 5-hydroxytryptamine receptors in human trigeminal ganglia and cerebral blood vessels. Mol Pharmacol 1996; 50: 219–223.Google Scholar
21. Longmore, J, Shaw, D, Smith, D, et al. Differential distribution of 5 HT1D.- and 5HT1B-immunoreactivity within the human trigemino-cerebrovascular system: implications for the discovery of new antimigraine drugs. Cephalalgia 1997; 17: 833–842.CrossRefGoogle Scholar
22. Maassen VanDenBrink, A, Reekers, M, Bax, WA, Ferrari, MD, Saxena PR. Coronary side-effect potential of current and prospective antimigraine drugs. Circulation 1998; 98: 25–30.Google Scholar
23. Durham, PL, Sharma, RV and Russo, AF. Repression of the calcitonin gene-related peptide promoter by 5-HT1 receptor activation. J Neurosci 1997;17:9545–9553.CrossRefGoogle ScholarPubMed
24. Pascual, J, del Arco, D, Romon, T, et al. Autoradiographic distribution of [3H]sumatriptan-binding sites in post-mortem human brain. Cephalalgia 1996; 16: 317–322.Google Scholar
25. Fozard, JR, Kalkman, HO. 5-Hydroxytryptamine (5-HT) and the initiation of migraine: new perspectives. Naunyn-Schmiedeberg’s Arch Pharmacol 1994; 350: 225–229.CrossRefGoogle ScholarPubMed
26. Kalkman, HO. Is migraine prophylactic activity caused by 5-HT2B or 5-HT2C receptor blockade? Life Sci 1994; 54: 641–644.Google Scholar
27. Schmuck, K, Ullmer, C, Kalkman, HO, Probst, A, Lubbert, H. Activation of meningeal 5-HT2B receptors: an early step in the generation of migraine headache? Eur J Neurosci 1996;8:959–967.Google Scholar
28. Bouchelet, I, Cohen, Z, Stanimirovic, D, Hamel, E. Endothelial 5-HT2B, but not 5-HT2C, receptors in human brain vessels: possible role in migraine headache. J Cereb Blood Flow Metab 1997; 17(Suppl 1): S351.Google Scholar
29. Wei, EP, Moskowitz, MA, Boccalini, P, Contos, HA. Calcitonin gene related peptide mediates nitroglycerin and sodium nitroprusside-induced vasodilation in feline cerebral arteries. Circ Res 1992; 70: 1313–1319.Google Scholar
30. Lassen, LH, Ashina, M, Christiansen, I, et al. Nitric oxide synthase inhibition: a new principle in the treatment of migraine attacks. Cephalalgia 1998; 18: 27–32.CrossRefGoogle ScholarPubMed
31. Cohen, Z, Bouchelet, I, Olivier, A, et al. Multiple microvascular and astroglial 5-hydroxytryptamine receptor subtypes in human brain: molecular and pharmacological characterization. J Cereb Blood Flow Metab 1999; 19: 908–917.CrossRefGoogle Scholar