The selective 5‐HT_1F receptor agonist lasmiditan inhibits trigeminal nociceptive processing: Implications for migraine and cluster headache

Abstract

Background and Purpose Lasmiditan is a novel selective 5‐HT1F receptor agonist, recently approved for acute treatment of migraine. 5‐HT1F receptors are widely expressed in the CNS and trigeminovascular system. Here, we have explored the therapeutic effects of 5‐HT1F receptor activation in preclinical models of migraine and cluster headache. Experimental Approach Electrical stimulation of the dura mater or the superior salivatory nucleus in anaesthetised rats evoked 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 explored the tissue distribution of mRNA for 5‐HT1F receptors in human post‐mortem tissue and of several 5‐HT1 receptor subtypes in specific tissue beds. Key Results 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, but had no effect on cranial autonomic activation. mRNA profiling in human tissue showed expression of the 5‐HT1F receptor in several structures relevant for migraine and cluster headache. Conclusion and Implications Our data suggest that lasmiditan acts, at least in part, as an anti‐migraine 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 support the potential utility of lasmiditan as a therapeutic option for the acute treatment of cluster headache attacks. 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

Meta-analysis of the effects of clinically-effective therapeutics in the preclinical migraine model as a tool for design optimisation

“…Regarding the pre-specified factors for subgroup analyses, authors of three studies supplemented the description of dural electrical stimulation (Summ et al (2021), Akerman and Romero-Reyes (2019), and Vila-Pueyo et al (2021) used threshold intensity); one author from our group also provided several poorly reported items for two studies (Sokolov et al (2008) used urethane and alpha-chloralose for anaesthesia maintenance; Sokolov et al (2013) used room air for artificial ventilation).…”

Meta‐analysis of the effects of anti‐migraine therapeutics in the rat trigeminovascular nociception model as a tool for design optimization

“…For each data set we calculated the percentage of variability that can be attributed to the overall heterogeneity (which is the sum of between-and within-study heterogeneity) rather than a chance (sample variance) using Higgins's I 2 (0%-25% was interpreted as very low heterogeneity; 25%-50% as low heterogeneity; 50%-75% as moderate heterogeneity; and >75% as high heterogeneity) and examined the distribution of variance over experiment level and study level (Viechtbauer, 2022). To refine the modelling of EMTVN and inform future studies, we assessed the extent to which methodological features listed in Table 2 and the reporting of measures to reduce bias (randomization, sample size calculation, similarity at baseline and blinding) explain the observed heterogeneity by subgroup analyses (meta-regression).…”

Epigenetic Connection of the Calcitonin Gene-Related Peptide and Its Potential in Migraine

“…This opened a perspective to consider the epigenetic regulation of CALCA in glial cells as a potential therapeutic target in migraine. The involvement of glial cells in migraine has been addressed in several studies and hypotheses (e.g., [ 130 , 131 , 132 ]), but mainly in the context of the role of glial cells in cortical-spreading depression. The action of antagonists of and antibodies against CGRP and its receptor also affects glial cells expressing the CALCA gene, but the problem of epigenetic regulation of this gene as a target in migraine prevention and therapy is still a perspective [ 133 ].…”