The selective 5-HT1F receptor agonist lasmiditan inhibits trigeminal nociceptive processing: implications for migraine and cluster headache

TY - JOUR

T1 - The selective 5-HT1F receptor agonist lasmiditan inhibits trigeminal nociceptive processing: implications for migraine and cluster headache

AU - Vila Pueyo, Marta

AU - Page, Keith

AU - Murdock, Paul

AU - Loraine, Howard

AU - Woodrooffe, Amanda

AU - Johnson, Kirk

AU - Goadsby, Peter

AU - Holland, Philip

N1 - Funding Information: M.V.‐P., K.P., P.R.M., H.J.L. and A.J.W. declare no competing financial interests. K.W.J. is an employee and stockholder of Eli Lilly and Company. P.J.G. reports, unrelated to the current project, grants and personal fees from Amgen and Celgene; personal fees from Alder Biopharmaceuticals, AEON Biopharma, Allergan, Biohaven Pharmaceuticals Inc., Clexio, Electrocore LLC, eNeura, Epalex, GlaxoSmithKline, Impel NeuroPharma, Lundbeck, Mundipharma, Novartis, Pfizer, Praxis, Sanofi, Santara Therapeutics, Satsuma, Teva Pharmaceuticals, Trigemina Inc. and W. L. Gore; personal fees for advice through Gerson Lehrman Group, LEK and Guidepoint; fees for educational materials from Massachusetts Medical Society, Medery, Medlink, PrimeEd, UptoDate and WebMD; publishing royalties from Oxford University Press and Wolters Kluwer; and medicolegal advice in headache and a patent magnetic stimulation for headache assigned to eNeura without fee. P.R.H. reports, unrelated to the current project, honoraria for educational and advisory purposes from Allergan, Novartis and Teva as well as research funding from Eli Lilly, Amgen and Cellgene/Bristol Myers Squibb. Publisher Copyright: © 2021 The British Pharmacological Society

PY - 2021/11/16

Y1 - 2021/11/16

N2 - Background and Purpose: Lasmiditan is a novel selective 5-HT 1F receptor agonist, recently approved for acute treatment of migraine. 5-HT 1F receptors are widely expressed in the CNS and trigeminovascular system. Here, we have explored the therapeutic effects of 5-HT 1F 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-HT 1F receptors in human post-mortem tissue and of several 5-HT 1 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-HT 1F 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.

AB - Background and Purpose: Lasmiditan is a novel selective 5-HT 1F receptor agonist, recently approved for acute treatment of migraine. 5-HT 1F receptors are widely expressed in the CNS and trigeminovascular system. Here, we have explored the therapeutic effects of 5-HT 1F 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-HT 1F receptors in human post-mortem tissue and of several 5-HT 1 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-HT 1F 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.

UR - http://www.scopus.com/inward/record.url?scp=85119146016&partnerID=8YFLogxK

U2 - 10.1111/bph.15699

DO - 10.1111/bph.15699

M3 - Article

SN - 0007-1188

JO - British journal of pharmacology

JF - British journal of pharmacology

ER -