Downregulation of C1C-3 in dorsal root ganglia neurons contributes to mechanical hypersensitivity following peripheral nerve injury
Downregulation of C1C-3 in dorsal root ganglia neurons contributes to mechanical hypersensitivity following peripheral nerve injury
复制标题
背根神经节神经元中 C1C-3 的下调导致周围神经损伤后的机械超敏反应
DOI：
10.1016/j.neuropharm.2016.07.023
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发表时间：
2016-11-01
影响因子：
4.7
通讯作者：
Liu, Xian-Guo
中科院分区：
文献类型：
--
作者：
Pang, Rui-Ping;Xie, Man-Xiu;Liu, Xian-Guo
C1 C-3氯离子通道/逆向转运蛋白在中枢神经系统突触传递中起重要作用。然而，其在感觉神经元中的表达和功能知之甚少。在目前的工作中，我们发现CIC-3在背根神经节（DRG）中高水平表达。免疫荧光共染色结果显示，CIC-3主要分布于A型和C型伤害性感受神经元。在神经病理性疼痛的备用神经损伤（SNI）模型中，DRG中的CIC-3表达降低。用siRNA敲低DRG神经元中的局部CIC-3增加了幼稚大鼠的机械敏感性，而过表达C1 C-3逆转了外周神经损伤后对机械刺激的超敏反应。此外，CIC-3的基因缺失增强了小鼠的机械敏感性，但不影响热阈值和冷阈值。CIC-3缺陷小鼠中CIC-3表达的恢复逆转了机械敏感性。从机制上讲，CIC-3的缺失通过增加DRG神经元的兴奋性来增强机械敏感性。这些数据表明，CIC-3是神经性疼痛发展的内源性抑制剂。周围神经损伤引起的CIC-3下调是机械性超敏反应的关键。我们的研究结果表明，CIC-3是一种新的治疗神经病理性疼痛的治疗靶点。(C)2016爱思唯尔有限公司版权所有
C1C-3 chloride channel/antiporter has been demonstrated to play an important role in synaptic transmission in central nervous system. However, its expression and function in sensory neurons is poorly understood. In present work, we found that CIC-3 is expressed at high levels in dorsal root ganglia (DRG). Co-immunofluorescent data showed that CIC-3 is mainly distributed in A- and C-type nociceptive neurons. CIC-3 expression in DRG is decreased in the spared nerve injury (SNI) model of neuropathic pain. Knockdown of local CIC-3 in DRG neurons with siRNA increased mechanical sensitivity in naive rats, while overexpression of C1C-3 reversed the hypersensitivity to mechanical stimuli after peripheral nerve injury. In addition, genetic deletion of CIC-3 enhances mouse mechanical sensitivity but did not affect thermal and cold threshold. Restoration of CIC-3 expression in CIC-3 deficient mice reversed the mechanical sensitivity. Mechanistically, loss of CIC-3 enhanced mechanical sensitivity through increasing the excitability of DRG neurons. These data indicate that CIC-3 is an endogenous inhibitor of neuropathic pain development. Downregulation of CIC-3 by peripheral nerve injury is critical for mechanical hypersensitivity. Our findings suggest that CIC-3 is a novel therapeutic target for treating neuropathic pain. (C) 2016 Elsevier Ltd. All rights reserved.