Evidence for orexinergic mechanisms in migraine
Evidence for orexinergic mechanisms in migraine
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DOI：
10.1016/j.nbd.2014.10.022
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发表时间：
2015-02-01
影响因子：
6.1
通讯作者：
Goadsby, Peter J.
中科院分区：
文献类型：
--
作者：
Hoffmann, Jan;Supronsinchai, Weera;Goadsby, Peter J.
目的：检查双重食欲素受体拮抗剂（DORA）的食欲素能阻滞对与偏头痛和偏头痛先兆相关的外周和中央三叉神经以及皮质激活实验模型的影响。方法：在本研究中，我们使用了suvorexant的前体，一种双重食欲素受体拮抗剂#12（DORA-12）在大鼠硬脑膜三叉神经血管伤害性感受的体内实验模型中。利用神经源性硬脑膜血管扩张和三叉神经鞘神经元电生理记录，直接研究三叉神经伤害性感受机制。KCl诱发的皮层扩散性抑制也被用作偏头痛aire.Results的替代品：神经原性诱导的血管扩张脑膜中动脉，三叉神经的外周传入投射的伤害性激活引起的，被衰减DORA-12静脉注射（1毫克公斤（-1））。静脉注射DORA-12（1 mg/kg）可显著抑制二阶三叉神经复合体神经元活动。DORA-12显着降低易感性KCl诱发皮层扩散性depresson.Conclusion：这项研究提供了第一个直接的证据，即同时拮抗两个食欲素受体能够减弱三叉神经伤害性活动，以及诱导升高的阈值诱导皮层扩散性抑制（CSD）。在临床背景下，这些数据意味着，针对下丘脑食欲素能系统可能提供一个全新的机制，预防性治疗偏头痛和无先兆。(C)2014 Elsevier Inc. All rights reserved.
Objective: To examine the effect of the orexinergic blockade with a dual orexin receptor antagonist (DORA) on experimental models of peripheral and central trigeminal as well as cortical activation relevant to migraine and migraine aura.Methods: In this study we used a precursor of suvorexant, a dual orexin receptor antagonist #12 (DORA-12) in established experimental in vivo models of dural trigeminovascular nociception in rat. Neurogenic dural vasodilation and electrophysiological recordings of second order trigeminocervical neurons were used to study trigeminal nociceptive mechanisms directly. KCl-evoked cortical spreading depression was also used as a surrogate for migraine aura.Results: Neurogenically-induced vasodilation of the middle meningeal artery, caused by nociceptive activation of peripheral afferent projections of the trigeminal nerve, was attenuated by intravenous DORA-12 (1 mg kg(-1)). Second-order trigeminocervical complex neuronal activity was significantly inhibited by intravenous DORA-12 (1 mg kg(-1)). DORA-12 significantly reduced susceptibility to KCl-evoked cortical spreading depression.Conclusion: The study provides the first direct evidence, that simultaneous antagonism on both orexin receptors is able to attenuate trigeminal nociceptive activity as well as to induce an elevation of the threshold for the induction of a cortical spreading depression (CSD). In the clinical context, these data imply that targeting the hypothalamic orexinergic system may offer an entirely novel mechanism for the preventive treatment of migraine with and without aura. (C) 2014 Elsevier Inc. All rights reserved.