Headache Group, Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
Cerevance, Cambridge, UK.
Br J Pharmacol. 2022 Feb;179(3):358-370. doi: 10.1111/bph.15699. Epub 2021 Nov 16.
Lasmiditan is a novel selective 5-HT receptor agonist, recently approved for acute treatment of migraine. 5-HT receptors are widely expressed in the CNS and trigeminovascular system. Here, we have explored the therapeutic effects of 5-HT receptor activation in preclinical models of migraine and cluster headache.
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 receptors 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, but had 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 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.
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.
拉米替坦是一种新型的选择性 5-HT 受体激动剂，最近被批准用于偏头痛的急性治疗。5-HT 受体广泛表达于中枢神经系统和三叉血管系统。在这里，我们研究了 5-HT 受体激活在偏头痛和丛集性头痛的临床前模型中的治疗效果。
在麻醉大鼠硬膜电刺激或上涎核刺激诱发三叉血管或三叉自主反射激活，在三叉颈复合体水平上测量颅自主表现，通过前脉络膜血流改变来测量。然后用拉米替坦对这些反应进行挑战。我们探索了人类死后组织中 5-HT 受体的 mRNA 组织分布，以及特定组织床中几种 5-HT 受体亚型的分布。
拉米替坦在偏头痛的临床前模型中剂量依赖性地降低了三叉血管激活。拉米替坦还降低了上涎核诱发的三叉自主反射激活，但对颅自主激活没有影响。人类组织的 mRNA 谱分析显示 5-HT 受体在与偏头痛和丛集性头痛相关的几个结构中表达。
我们的数据表明，拉米替坦通过降低三叉血管激活，至少部分作用于偏头痛的治疗。此外，我们的结果突出了拉米替坦在丛集性头痛的临床前模型中具有明确的作用。鉴于该模型已被证实具有良好的转化效果，我们的数据支持拉米替坦作为治疗丛集性头痛急性发作的一种治疗选择的潜在效用。
本文是一个关于偏头痛和头痛治疗进展的专题（BJP 75 周年纪念）的一部分。要查看本部分的其他文章，请访问 http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.3/issuetoc.
