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大鼠背根节慢性压迫或急性分离引起的cGMP-PKG信号通路持续激活介导背根节神经元的异常兴奋性和痛觉过敏

黄志江, 李浩川, 刘苏, 宋学军^*

帕克大学帕克研究所，德克萨斯州达拉斯市 75229，美国

摘要

背根节(dorsal root ganglion, DRG)损伤或炎症可导致DRG神经元兴奋性异常增强和痛觉过敏。我们近期研究显示，长期慢性在体压迫(chronic compression of DRG, CCD)或急性离体分离(acute dissociation of DRG, ADD)背根节导致的神经元兴奋性异常增强和痛觉过敏受环鸟苷酸(cGMP)-蛋白激酶G (PKG)信号通路活动的调控。本研究采用大鼠CCD模型和ADD模型，直接在DRG上检测cGMP浓度和PKG mRNA及其蛋白质的表达，进一步证明了cGMP-PKG信号通路活动在CCD和ADD DRG所致神经元兴奋性异常增强和痛觉过敏中的重要作用。酶联免疫吸附测定(ELISA)和逆转录聚合酶链反应(RT-PCR)的实验结果显示，CCD或ADD明显增高DRG内的cGMP浓度，上调I型PKG mRNA和PKG蛋白质表达。电生理膜片钳全细胞记录结果显示，CCD和ADD显著增强伤害特异性DRG细胞的兴奋性及其对cGMP-PKG信号通路激动剂的反应强度。增强的细胞兴奋性可以被cGMP-PKG通路阻断剂所抑制。在体压迫DRG的椎间孔内注射cGMP-PKG抑制剂显著减轻痛觉过敏。以上研究结果表明，CCD和ADD可以激活DRG细胞内的cGMP-PKG信号通路，而损伤的DRG细胞的超兴奋性和痛觉过敏的维持则需要cGMP-PKG信号通路处于持续的激活状态。

关键词： 慢性压迫; 急性分离; 背根节; 超兴奋性; 痛觉过敏; 环鸟苷酸; 蛋白激酶G

分类号：R338.1+1

Activation of cGMP-PKG signaling pathway contributes to neuronal hyperexcitability and hyperalgesia after in vivo prolonged compression or in vitro acute dissociation of dorsal root ganglion in rats

HUANG Zhi-Jiang, LI Hao-Chuan, LIU Su, SONG Xue-Jun^*

Department of Neurobiology, Parker Research Institute, Parker University, 2540 Walnut Hill Lane, Dallas, Texas, 75229 USA

Abstract

Injury or inflammation affecting sensory neurons in the dorsal root ganglia (DRG) causes hyperexcitability of DRG neurons that can lead to spinal central sensitization and neuropathic pain. Recent studies have indicated that, following chronic compression of DRG (CCD) or acute dissociation of DRG (ADD) treatment, both hyperexcitability of neurons in intact DRG and behaviorally expressed hyperalgesia are maintained by activity in cGMP-PKG signaling pathway. Here, we provide evidence supporting the idea that CCD or ADD treatment activates cGMP-PKA signaling pathway in the DRG neurons. The results showed that CCD or ADD results in increase of levels of cGMP concentration and expression of PKG-I mRNA, as well as PKG-I protein in DRG. CCD or ADD treated-DRG neurons become hyperexcitable and exhibit increased responsiveness to the activators of cGMP-PKG pathway, 8-Br-cGMP and Sp-cGMP. Hyperexcitability of the injured neurons is inhibited by cGMP-PKG pathway inhibitors, ODQ and Rp-8-pCPT-cGMPS. In vivo delivery of Rp-8-pCPT-cGMPS into the compressed ganglion within the intervertebral foramen suppresses CCD-induced thermal hyperalgesia. These findings indicate that the in vivo CCD or in vitro ADD treatment can activate the cGMP-PKG signaling pathway, and that continuing activation of cGMP-PKG pathway is required to maintain DRG neuronal hyperexcitability and/or hyperalgesia after these two dissimilar forms of injury-related stress.

Key words: compression; dissociation; dorsal root ganglion; hyperexcitability; hyperalgesia; cGMP; PKG

收稿日期：2012-08-05　　录用日期：2012-08-30

通讯作者：宋学军　　E-mail: song@parker.edu

引用本文：

黄志江, 李浩川, 刘苏, 宋学军. 大鼠背根节慢性压迫或急性分离引起的cGMP-PKG信号通路持续激活介导背根节神经元的异常兴奋性和痛觉过敏[J]. 生理学报 2012; 64 (5): 563-576.

HUANG Zhi-Jiang, LI Hao-Chuan, LIU Su, SONG Xue-Jun. Activation of cGMP-PKG signaling pathway contributes to neuronal hyperexcitability and hyperalgesia after in vivo prolonged compression or in vitro acute dissociation of dorsal root ganglion in rats. Acta Physiol Sin 2012; 64 (5): 563-576 (in Chinese with English abstract).