Neuronal PAC1 receptors mediate delayed activation and sensitization of trigeminocervical neurons: Relevance to migraine
Neuronal PAC1 receptors mediate delayed activation and sensitization of trigeminocervical neurons: Relevance to migraine
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DOI：
10.1126/scitranslmed.aaa7557
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发表时间：
2015-10-07
影响因子：
17.1
通讯作者：
Goadsby, Peter J.
中科院分区：
文献类型：
--
作者：
Akerman, Simon;Goadsby, Peter J.
偏头痛的发病机制尚不清楚。为了剖析内源性外周和中枢机制在引发偏头痛中的相对贡献，我们检查了两种药理学相似但临床不同的血管舒张神经肽、血管活性肠肽（VIP）和垂体腺苷酸环化酶激活肽38（PACAP-38）对硬脑膜脑膜血管和中枢三叉血管神经元的反应特性的影响。 VIP 和 PACAP-38 均引起 VPAC2 受体介导的短暂脑膜血管舒张，这与中枢三叉血管神经元的激活不一致。只有 PACAP-38 引起中枢三叉血管神经元的延迟激活和敏化，类似于其诱发偏头痛的延迟效应。延迟 90 分钟后，PACAP-38 诱导持续自发放电和对颅内和颅外体感刺激的超敏性大幅增加，这与脑膜血管舒张并不相符。仅静脉注射 PAC1 受体拮抗剂可抑制硬脑膜三叉血管伤害感受的外周脑膜血管舒张作用，而仅中枢（脑室内）施用 PAC1 受体拮抗剂可抑制中央三叉血管神经元中硬脑膜伤害感受诱发的动作电位。我们的数据表明，偏头痛发病机制的内源性机制位于中枢神经系统内，可能位于三叉颈复合体中，并且硬脑膜及其主要传入神经支配不太可能导致偏头痛的发生。此外，PAC1 受体可能是偏头痛治疗的合适分子靶点。
The pathogenesis of migraine is not well understood. To dissect the relative contributions of endogenous peripheral and central mechanisms in triggering migraine, we examined the effects of two pharmacologically similar, but clinically different, vasodilator neuropeptides, vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide 38 (PACAP-38), on dural meningeal vessels and the response properties of central trigeminovascular neurons. Both VIP and PACAP-38 caused short-lived meningeal vasodilation mediated by VPAC2 receptors, which did not coincide with activation of central trigeminovascular neurons. Only PACAP-38 caused delayed activation and sensitization of central trigeminovascular neurons, similar to its delayed effects in inducing migraine headache. After a 90-min delay, PACAP-38 induced a robust increase in ongoing spontaneous firing and hypersensitivity to intra-and extracranial somatosensory stimulation, which did not coincide with meningeal vasodilation. Only intravenous delivery of a PAC1 receptor antagonist inhibited the peripheral meningeal vasodilatory effects of dural trigeminovascular nociception, whereas only central (intracerebroventricular) administration of the PAC1 receptor antagonist inhibited dural nociceptive-evoked action potentials in central trigeminovascular neurons. Our data suggest that the endogenous mechanisms of migraine pathogenesis are located within the central nervous system, likely in the trigeminocervical complex, and that the dural meninges and their primary afferent innervation are less likely to contribute to migraine initiation. Furthermore, the PAC1 receptor may be an appropriate molecular target for migraine therapeutics.