Atogepant - an orally-administered CGRP antagonist - attenuates activation of meningeal nociceptors by CSD.
Atogepant - an orally-administered CGRP antagonist - attenuates activation of meningeal nociceptors by CSD.
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DOI：
10.1177/03331024221083544
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发表时间：
2022-08
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影响因子：
--
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--
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本研究通过评估atogepant对皮层扩散性抑制（CSD）后机械敏感性C-和Aδ -脑膜伤害感受器激活的影响，研究了atogepant的作用机制，atogepant是一种最近批准用于预防性治疗发作性偏头痛的小分子CGRP受体拮抗剂。三叉神经节神经元的单单位记录（32个Aδ和20个C-纤维）用于记录口服施用的atogepant（5 mg/kg）或赋形剂对麻醉的雄性大鼠中CSD诱导的激活的影响。时间效应的贝叶斯分析发现atogepant在测试剂量下不能完全阻止伤害感受器的激活，但在CSD诱导后的不同时间间隔，它显著降低了C-和Aδ -纤维的反应幅度和反应概率。对于C-纤维，反应的减少在早期（第一小时）是显著的，但在激活的延迟阶段，而在Aδ -纤维，激活的显著减少在延迟（第二和第三小时）是明显的，但在激活的早期阶段。这些发现确定了atogepant（一种小分子CGRP拮抗剂（部分抑制Aδ和C纤维））与先前发现的fremanezumab（一种CGRP靶向抗体（仅抑制Aδ纤维）和onabotulinumtoxinA（仅抑制C纤维））的作用之间的差异-表明这些药物在预防性治疗偏头痛的机制上不同
This study investigated mechanism of action of atogepant, a small-molecule CGRP receptor antagonist recently approved for preventive treatment of episodic migraine, by assessing its effect on activation of mechanosensitive C- and Aδ -meningeal nociceptors following cortical spreading depression (CSD). Single-unit recordings of trigeminal ganglion neurons (32 Aδ and 20 C-fibers) innervating the dura was used to document effects of orally administered atogepant (5mg/kg) or vehicle on CSD-induced activation in anesthetized male rats Bayesian analysis of time effects found that atogepant did not completely prevent the activation of nociceptors at the tested dose, but it significantly reduced response amplitude and probability of response in both the C- and the Aδ -fibers at different time intervals following CSD induction. For C-fibers, the reduction in responses was significant in the early (first hour), but not delayed phase of activation, whereas in Aδ -fibers, significant reduction in activation was apparent in the delayed (second and third hours) but not early phase of activation. These findings identify differences between the actions of atogepant, a small molecule CGRP antagonist (partially inhibiting both Aδ and C-fibers) and those found previously for fremanezumab, a CGRP-targeted antibody (inhibiting Aδ fibers only) and onabotulinumtoxinA (inhibiting C-fibers only)- suggesting that these agents differ in their mechanisms for the preventive treatment of migraine
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DOI：
10.1177/0333102420983282
发表时间：
2021-04
期刊：
Cephalalgia : an international journal of headache
影响因子：
--
作者：
Bhakta M;Vuong T;Taura T;Wilson DS;Stratton JR;Mackenzie KD
通讯作者：
Mackenzie KD
影响因子：
4.9
作者：
Kopruszinski, Caroline Machado;Xie, Jennifer Yanhua;Porreca, Frank
通讯作者：
Porreca, Frank
影响因子：
4.9
作者：
Christensen, Sarah L.;Ernstsen, Charlotte;Kristensen, David M.
通讯作者：
Kristensen, David M.
影响因子：
4.9
作者：
Filiz, Asli;Tepe, Nermin;Bolay, Hayrunnisa
通讯作者：
Bolay, Hayrunnisa
影响因子：
3.1
作者：
Edvinsson, Lars;Grell, Anne-Sofie;Warfvinge, Karin
通讯作者：
Warfvinge, Karin