5‐hydroxytryptamine in migraine: The puzzling role of ionotropic 5‐HT₃ receptor in the context of established therapeutic effect of metabotropic 5‐HT₁ subtypes

5‐hydroxytryptamine (5‐HT; serotonin) is traditionally considered as a key mediator implicated in migraine. Multiple 5‐HT receptor subtypes contribute to a variety of region‐specific functional effects. The raphé nuclei control nociceptive inputs by releasing 5‐HT in the brainstem, whereas dural mast cells provide the humoral source of 5‐HT in the meninges. Triptans (5‐HT 1B/D agonists) and ditans (5‐HT 1F agonists) are the best established 5‐HT anti‐migraine agents. However, activation of meningeal afferents via ionotropic 5‐HT 3 receptors results in long‐lasting excitatory drive suggesting a pro‐nociceptive role for these receptors in migraine. Nevertheless, clinical data do not clearly support the applicability of currently available 5‐HT 3 antagonists to migraine treatment. The reasons for this might be the presence of 5‐HT 3 receptors on inhibitory interneurons dampening the excitatory drive, a lack of 5‐HT 3 A–E subunit‐selective antagonists and gender/age‐dependent effects. This review is focusing on the controversial role of 5‐HT 3 receptors in migraine pathology and related pharmacological perspectives of 5‐HT ligands. LINKED ARTICLES This article is part of a themed issue on Advances in Migraine and Headache Therapy (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.3/issuetoc

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