5-HT2 receptor antagonists and migraine therapy

Abstract

5-Hydroxytryptamine (5-HT; serotonin) has been implicated in the pathophysiology of migraine, and several drugs with potent 5-HT2 receptor blocking activity (methysergide, pizotifen, cyproheptadine and mianserin) have been recognized as being clinically effective in migraine prophylaxis, although the selective 5-HT2 receptor antagonist ketanserin (the principal agent used to identify 5-HT2 receptor-mediated actions) seems to be ineffective in migraine. Pizotifen is the most widely used 5-HT2 receptor antagonist in migraine prophylaxis, because of its superior efficacy compared with cyproheptadine, and because the incidence and severity of adverse effects with pizotifen is lower compared with methysergide and mianserin. These agents have additional antagonistic effects at histamine H1, muscarinic cholinergic, alpha 1-adrenergic, alpha 2-adrenergic and dopamine receptors, but drugs which are selective for these non-5-HT receptors appear to be of no benefit in migraine. Actions mediated by 5-HT2 receptors which could be of relevance to migraine comprise cranial vasoconstriction, increased cranial capillary permeability and platelet aggregation, and some central nervous system effects and neuroendocrine functions. Although pizotifen, cyproheptadine and mianserin are considered to be relatively specific for 5-HT2 receptors, these agents and methysergide all share a high affinity for 5-HT1C binding sites; ketanserin, however, has little affinity for these sites, thus activation of 5-HT1C receptors may be an important step in the pathogenesis of migraine. It is not yet known which 5-HT1C receptor-mediated actions of 5-HT are relevant to migraine, but some behavioural actions and cranial vasodilatation via release of endothelium-derived relaxing factor may be involved.(ABSTRACT TRUNCATED AT 250 WORDS)

Bovine isolated middle cerebral artery contractions to antimigraine drugs

“…Instead, the potency of ketanserin to antagonise 5-HT was assessed by calculating its pK B on the basis of the concentration response curves to 5-HT in the absence (control) and presence of 10 nM ketanserin which fitted well to a monophasic model. The derived pEC 50 values (6.8±0.2 and 6.2±0.1, respectively) yielded a pK B of 8.4±0.3, which is in the same range as other reports on the potency of ketanserin at the 5-HT 2 receptor (pA 2 /pK B : 8.1-10.4, Mylecharane 1991).…”

Nuclear factor‐κB as a molecular target for migraine therapy

“…2 In addition, NO is generated within cerebral blood vessels by activation of 5-hydroxytryptamine (5-HT) 2B receptors, and receptor blockers are given to patients to suppress attacks prophylactically. 3,4 Typical migraine headaches are provoked 4 to 6 hours after GTN infusion in two-thirds of migraineurs, and headaches have been described in workers exposed to GTN in explosives factories. 5,6 Finally, the administration of an NOS inhibitor improves symptoms significantly in two-thirds of subjects during an acute attack.…”

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