Are 5-HT1 receptor agonists effective anti-migraine drugs?

Abstract

Nearly 30 years have passed since the first selective 5-HT1 receptor agonist sumatriptan became a choice of treatment for migraineurs. Recently, a new class of antimigraine drugs has joined antimigraine armamentarium, targeting the calcitonin generelated peptide (CGRP) receptor; however, 5-HT1 receptor agonists remain a mainstream of migraine therapy and antimigraine drug research. This editorial discusses 5-HT1 receptor agonists approved for clinical use, the pathogenesis of migraine, and the tryptophan (TRP)-kynurenine (KYN) pathway that imposes a significant impact on serotonin metabolism and thus migraine, in search of a novel target for the treatment of migraine. Migraine is a prevalent and debilitating neurological disorder that causes throbbing headache and pulsatile sensation, often accompanied by nausea, vomiting, numbness, tingling, and severe sensitivity to light and sound. The global prevalence of migraine is 14.7%; it is three times more common in women than men; and women are less responsive to treatment. A migraine attack may last 72 h. Migraine is attributed to complex multifactorial conditions with underlying heterogeneity, which arise to considerable variations of inter-patient and longitudinal intra-patient responses to treatments. The first-line treatment for mild to moderate migraine is acetaminophen and nonsteroidal anti-inflammatory drugs, while the first-line treatment for mild to severe migraine is triptans, a group of the indole ring-containing tryptamine-based compounds which act as agonists for serotonin (5-hydroxytryptamine) 5-HT1B and 5-HT1D receptors. Sumatriptan is the first antimigraine drug that belongs to this family and is available in tablet, nasal spray, and subcutaneous injection. Previously, the action mechanism of the triptans was considered to be attributed to their vasoconstrictive properties in the central nervous system. However, a selective 5-HT1F receptor agonist lasmiditan lacks vasoconstrictive properties. Lasmiditan was approved for clinical use in 2019 by the US Food and Drug Administration and is a choice of treatment for migraineurs refractory to the triptans or having cardiovascular diseases, but the mechanism of its antimigraine action remains unclear [1]. Recently a new class of drugs joined the repertoire of antimigraine treatment. Rimegepant and ubrogepant are CGRP receptor antagonists, while humanized CGRP monoclonal antibodies include erenumab, fremanezumab, and galcanezumab. Triptans and lasmiditan are used for the treatment of acute attack; the gepants both for an acute attack and prevention; and CGRP receptor antibodies for prevention. They are indicated for the prevention of episodic or chronic migraine in adults [2]. Nevertheless, 5-HT1 receptor agonists have been a mainstream for antimigraine drug research, but little is known about the exact mechanism of action of antimigraine 5-HT1 receptor agonists.