Calcium Channel α2δ1 Subunit Mediates Secondary Orofacial Hyperalgesia Through PKC-TRPA1/Gap Junction Signaling
Calcium Channel α2δ1 Subunit Mediates Secondary Orofacial Hyperalgesia Through PKC-TRPA1/Gap Junction Signaling
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DOI：
10.1016/j.jpain.2019.08.012
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发表时间：
2020-01-01
期刊：
影响因子：
4
通讯作者：
Wang, Yan-Qing
中科院分区：
文献类型：
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作者：
Cui, Wen-Qiang;Chu, Yu-Xia;Wang, Yan-Qing
口面部疼痛的特点是容易扩散到邻近区域，因此表现为原发性痛觉过敏（受伤部位的过敏）和继发性痛觉过敏（受伤区域外的域外过敏）。然而，人们对继发性痛觉过敏背后的机制知之甚少。在本研究中，我们使用眶下神经部分横断的小鼠模型（pT-ION）来研究钙通道亚基α2δ1（Cavα2δ1）及其下游信号传导是否有助于口面部区域继发性痛觉过敏的发生。 pT-ION 引起原发性（V2 皮肤）和继发性（V3 皮肤）痛觉过敏，这种情况可被 Cav α2 δ 1 拮抗剂加巴喷丁和三叉神经节 (TG)-V3 神经元中的 Cav α2 δ 1 靶向干扰 RNA 的表达所逆转。 pT-ION 诱导 PKC 和 TRPA1 表达增加，这种表达可被 Cav α 2 delta 1 靶向干扰 RNA 逆转，并且 PKC 抑制逆转 pT-ION 诱导的 TRPA1 和间隙连接 (GJ) 蛋白的上调。 TG-V2 神经元中的 Cav α 2 δ 1 过表达诱导 TG 和三叉神经尾亚核中 PKC、TRPA1 和 GJ 蛋白的上调，并诱导 V3 皮肤区域的超敏反应，而 TRPA1、GJ 或 PKC 阻断可逆转这种情况。因此，我们得出结论，Cav α 2 δ 1 通过其下游 PKC-TRPA1/GJ 信号通路促进继发性痛觉过敏的发生。 观点：本研究表明，Cav α 2 delta 1 和下游 PKC-TRPA1/GJ 信号通路的激活对三叉神经损伤引起的继发性机械和冷痛觉过敏有很大贡献。这表明 Cav α 2 delta 1、TRPA1 或 GJ 的抑制剂可能是治疗神经损伤引起的口面部疼痛扩散的有效方法。 (C) 2020 年美国疼痛研究协会。由爱思唯尔公司出版。保留所有权利。
Orofacial pain is characterized by its easy spread to adjacent areas, thus presenting with primary hyperalgesia (hypersensitivity at the site of injury) and secondary hyperalgesia (extraterritorial hypersensitivity outside the injured zone). However, the mechanisms behind the secondary hyperalgesia are poorly understood. In the present study, we used a mouse model of partial transection of the infraorbital nerve (pT-ION) to study whether calcium channel subunit alpha 2 delta 1 (Cav alpha 2 delta 1) and its downstream signaling contributes to the development of secondary hyperalgesia in the orofacial area. pT-ION caused primary (V2 skin) and secondary (V3 skin) hyperalgesia, which was reversed by the Cav alpha 2 delta 1 antagonist gabapentin and by the expression of Cav alpha 2 delta 1-targeting interfering RNA in trigeminal ganglion (TG)-V3 neurons. pT-ION induced increased expression of PKC and TRPA1, which was reversed by Cav alpha 2 delta 1-targeting interfering RNA, and PKC inhibition reversed the upregulation of TRPA1 and gap junction (GJ) proteins induced by pT-ION. Cav alpha 2 delta 1 overexpression in TG-V2 neurons induced the upregulation of PKC, TRPA1, and the GJ proteins in the TG and trigeminal subnucleus caudalis and induced hypersensitivity in the V3 skin area, which was reversed by TRPA1, GJ, or PKC blockade. Thus, we conclude that Cav alpha 2 delta 1 contributes to the development of secondary hyperalgesia through its downstream PKC-TRPA1/GJ signaling pathways.Perspective: This study demonstrates that the activation of Cav alpha 2 delta 1 and the downstream PKC-TRPA1/GJ signaling pathway contributes greatly to trigeminal nerve injury-induced secondary mechanical and cold hyperalgesia. This suggests that inhibitors of Cav alpha 2 delta 1, TRPA1, or GJs might be effective treatments for nerve injury-induced spreading of orofacial pain. (C) 2020 U.S. Association for the Study of Pain. Published by Elsevier Inc. All rights reserved.