Lasmiditan inhibits calcitonin gene-related peptide release in the rodent trigeminovascular system

被引：73

作者：

Labastida-Ramirez, Alejandro ^{[1
]}

Rubio-Beltran, Eloisa ^{[1
]}

Haanes, Kristian A. ^{[1
]}

Chan, Kayi Y. ^{[1
]}

Garrelds, Ingrid M. ^{[1
]}

Johnson, Kirk W. ^{[2
]}

Danser, Alexander H. J. ^{[1
]}

Villalon, Carlos M. ^{[3
]}

MaassenVanDenBrink, Antoinette ^{[1
]}

机构：

[1] Erasmus MC, Dept Internal Med, Div Pharmacol, Rotterdam, Netherlands

[2] Eli Lilly & Co, Lilly Corp Ctr, Indianapolis, IN 46285 USA

[3] Cinvestav Coapa, Dept Pharmacobiol, Ciudad De Mexico, Mexico

来源：

PAIN | 2020年 / 161卷 / 05期

关键词：

5-HT1F receptors; CGRP; Lasmiditan; Migraine; Trigeminovascular system; 5-HT1F RECEPTOR; SEROTONIN RECEPTOR; MOLECULAR-CLONING; MESSENGER-RNA; SUBSTANCE-P; RAT; MIGRAINE; CGRP; SUMATRIPTAN; EXPRESSION;

D O I：

10.1097/j.pain.0000000000001801

中图分类号：

R614 [麻醉学];

学科分类号：

100217 ;

摘要：

Migraine headache pathophysiology involves trigeminovascular system activation, calcitonin gene-related peptide (CGRP) release, and dysfunctional nociceptive transmission. Triptans are 5-HT1B/1D/(1F) receptor agonists that prejunctionally inhibit trigeminal CGRP release, but their vasoconstrictor properties limit their use in migraine patients with cardiovascular disease. By contrast, lasmiditan is a novel antimigraine and selective 5-HT1F receptor agonist devoid of vasoconstrictor properties. On this basis, this study has investigated the modulation of trigeminal CGRP release by lasmiditan. For this purpose, we have comparatively analysed the inhibition of several components of the trigeminovascular system induced by lasmiditan and sumatriptan through: ex vivo KCl-induced CGRP release from isolated dura mater, trigeminal ganglion, and trigeminal nucleus caudalis of mice; and in vivo dural vasodilation in the rat closed-cranial window model induced by endogenous (electrical stimulation and capsaicin) and exogenous CGRP. The ex vivo release of CGRP was similarly inhibited by sumatriptan and lasmiditan in all trigeminovascular system components. In vivo, intravenous (i.v.) lasmiditan or higher doses of sumatriptan significantly attenuated the vasodilatory responses to endogenous CGRP release, but not exogenous CGRP effects. These data suggest that lasmiditan prejunctionally inhibits CGRP release in peripheral and central trigeminal nerve terminals. Because lasmiditan is a lipophilic drug that crosses the blood-brain barrier, additional central sites of action remain to be determined.

引用

页码：1092 / 1099

页数：8

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