Dynamic changes in CGRP, PACAP, and PACAP receptors in the trigeminovascular system of a novel repetitive electrical stimulation rat model: Relevant to migraine
Dynamic changes in CGRP, PACAP, and PACAP receptors in the trigeminovascular system of a novel repetitive electrical stimulation rat model: Relevant to migraine
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新型重复电刺激大鼠模型三叉神经血管系统中 CGRP、PACAP 和 PACAP 受体的动态变化：与偏头痛相关
DOI：
10.1177/1744806918820452
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发表时间：
--
期刊：
影响因子：
3.3
通讯作者：
Yu shengyuan
中科院分区：
文献类型：
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作者：
Zhang qing;Han xun;Wu hangfei;Zhang mingjie;Hu guanqun;Dong zhao;Yu shengyuan
偏头痛是全球第七大致残疾病，全球患病率为11.7%。其主要机制之一是三叉神经血管系统的激活，而降钙素基因相关肽（CGRP）是该系统中偏头痛的重要治疗靶点。最近的研究表明垂体腺苷酸环化酶激活肽（PACAP）在偏头痛中的作用正在显现。然而，CGRP与PACAP之间的关系以及PACAP在偏头痛中的作用尚不明确。在这项研究中，我们通过刺激有意识大鼠的硬脑膜，建立了一种新的重复（1、3和7天）电刺激模型。然后，我们确定了三叉神经节和三叉神经血管系统的三叉神经尾核的表达模式。电刺激使面部力学阈值降低，敏感性顺序为：振动垫>内眼角>外眼角（P < 0.001）。电刺激组有转头、弹头的伤害行为（P < 0.05）。重要的是，电刺激增加了三叉神经节和三叉尾核中CGRP、PACAP和PACAP偏好型1 （PAC1）受体的表达（P < 0.05）。两种血管活性肠肽（VIP）共享型2 （VPAC1和VPAC2）受体在三叉神经节中的表达增加，而在三叉尾核中的表达在第3天达到峰值，第7天下降。PACAP与神经元核（NeuN）、PAC1和CGRP共定位于三叉神经节和三叉尾核。我们的研究结果表明，重复电刺激模型可以模拟偏头痛慢性化过程中的异常性疼痛，PACAP可能通过PAC1受体在偏头痛的发病机制中发挥作用。
Migraine is the seventh most disabling disorder globally, with prevalence of 11.7% worldwide. One of the prevailing mechanisms is the activation of the trigeminovascular system, and calcitonin gene-related peptide (CGRP) is an important therapeutic target for migraine in this system. Recent studies suggested an emerging role of pituitary adenylate cyclase-activating peptide (PACAP) in migraine. However, the relation between CGRP and PACAP and the role of PACAP in migraine remain undefined. In this study, we established a novel repetitive (one, three, and seven days) electrical stimulation model by stimulating dura mater in conscious rats. Then, we determined expression patterns in the trigeminal ganglion and the trigeminal nucleus caudalis of the trigeminovascular system. Electrical stimulation decreased facial mechanical thresholds, and the order of sensitivity was as follows: vibrissal pad >inner canthus >outer canthus (P < 0.001). The electrical stimulation group exhibited head-turning and head-flicks (P < 0.05) nociceptive behaviors. Importantly, electrical stimulation increased the expressions of CGRP, PACAP, and the PACAP-preferring type 1 (PAC1) receptor in both trigeminal ganglion and trigeminal nucleus caudalis (P < 0.05). The expressions of two vasoactive intestinal peptide (VIP)-shared type 2 (VPAC1 and VPAC2) receptors were increased in the trigeminal ganglion, whereas in the trigeminal nucleus caudalis, their increases were peaked on Day 3 and then decreased by Day 7. PACAP was colocalized with NEUronal Nuclei (NeuN), PAC1, and CGRP in both trigeminal ganglion and the trigeminal nucleus caudalis. Our results demonstrate that the repetitive electrical stimulation model can simulate the allodynia during the migraine chronification, and PACAP plays a role in the pathogenesis of migraine potentially via PAC1 receptor.