Proc. West. Pharmacol. Soc. 45: 199-210 (2002) An Introduction to Migraine: from Ancient Treatment to Functional Pharmacology and Antimigraine Therapy C.M. VILLALÓN*, D. CENTURIÓN, L.F. VALDIVIA, P. DE VRIES 1 & P.R. SAXENA 1 Depto de Farmacobiología, CINVESTAV-IPN, Czda. de los Tenorios 235, Col. Granjas Coapa, Deleg. Tlalpan, C.P. 14330, México D.F., México; 1 Department of Pharmacology, Erasmus University Medical Centre Rotterdam “EMCR”, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands *e-mail: carlos_villalon@infosel.net.mx SUMMARY: Migraine treatment has evolved from the realms of the supernatural into the scientific arena, but it seems still controversial whether migraine is primarily a vascular or a neurological dysfunction. Irrespective of this controversy, the levels of serotonin (5-hydroxytryptamine; 5-HT), a vasoconstrictor and a central neurotransmitter, seem to decrease during migraine (with associated carotid vasodilatation) whereas an iv infusion of 5-HT can abort migraine. In fact, 5-HT as well as ergotamine, dihydroer- gotamine and other antimigraine agents invariably pro- duce vasoconstriction in the external carotid circulation. The last decade has witnessed the advent of sumatriptan and second generation triptans (e.g. zolmitriptan, rizatrip- tan, naratriptan), which belong to a new class of drugs, now known as 5-HT 1B/1D/1F receptor agonists. Compared to sumatriptan, the second-generation triptans have a higher oral bioavailability and longer plasma half-life. In line with the vascular and neurogenic theories of mi- graine, all triptans produce selective carotid vasoconstric- tion (via 5-HT 1B receptors) and presynaptic inhibition of the trigeminovascular inflammatory responses implicated in migraine (via 5-HT 1D /5-ht 1F receptors). Moreover, se- lective agonists at 5-HT 1D (PNU-142633) and 5-ht 1F (LY344864) receptors inhibit the trigeminovascular sys- tem without producing vasoconstriction. Nevertheless, PNU-142633 proved to be ineffective in the acute treat- ment of migraine, whilst LY344864 did show some effi- cacy when used in doses which interact with 5-HT 1B re- ceptors. Finally, although the triptans are effective an- timigraine agents producing selective cranial vasocon- striction, efforts are being made to develop other effective antimigraine alternatives acting via the direct blockade of vasodilator mechanisms (e.g. antagonists at CGRP recep- tors, antagonists at 5-HT 7 receptors, inhibitors of nitric oxide biosynthesis, etc). These alternatives will hopefully lead to fewer side-effects. INTRODUCTION: Migraine is a specific syndrome that affects a significant fraction of the world population, with a higher prevalence in females (15%) than in males (6%) [1]. This syndrome is characterized by an intense and throbbing unilateral headache associated with anorexia, nausea, vomiting, photophobia, phonophobia and/or diar- rhea (common migraine). Sometimes the headache may be preceded by a focal neurological phenomenon (“aura”) followed by headache (classical migraine); this aura con- sists of certain motor (weakness or paralysis) and/or focal neurological (scintillating scotoma) symptoms. Figure 1. Ancient methods attempting to alleviate or cure headache: Top: Neolithic trepanation (8000 BC) which may have been performed to release demons and evil spirits from the head; Bottom: Egyptian papyrus (2500 BC) which describes bandaging a clay crocodile (with herbs stuffed into its mouth) to the head of the sufferer and praying. 199