Lasmiditan is a novel selective 5-HT receptor agonist, recently approved for the acute treatment of migraine. 5-HT receptors are widely expressed in the CNS and trigeminovascular system. Herein, we sought to explore the therapeutic effect of 5-HT receptor activation in preclinical models of migraine and cluster headache.
Anesthetised rats were surgically prepared for electrical stimulation of the dura mater or the superior salivatory nucleus to evoke trigeminovascular or trigeminal-autonomic reflex activation at the level of the trigeminocervical complex. Additionally, cranial autonomic manifestations in response to trigeminal-autonomic reflex activation were measured, via anterior choroidal blood flow alterations. These responses were then challenged with lasmiditan. We then explored the tissue distribution of the 5-HT receptor mRNA in human post-mortem tissue and of several 5-HT receptor subtypes in specific tissue beds.
Lasmiditan dose-dependently reduced trigeminovascular activation in a preclinical model of migraine. Lasmiditan also reduced superior salivatory nucleus-evoked activation of the trigeminal-autonomic reflex, while having no effect on cranial autonomic activation. mRNA profiling in human tissue showed expression of the 5-HT receptor in several structures relevant for migraine and cluster headache.
Our data suggest that lasmiditan acts at least in part as an antimigraine agent by reducing trigeminovascular activation. Furthermore, our results highlight a clear action for lasmiditan in a preclinical model of cluster headache. Given the proven translational efficacy of this model, our data supports the potential utility of lasmiditan as a therapeutic option for the acute treatment of cluster headache attacks.

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