Reopening of ATP-sensitive potassium channels reduces neuropathic pain and regulates astroglial gap junctions in the rat spinal cord

被引:67
|
作者
Wu, Xue-Feng [1 ,2 ]
Liu, Wen-Tao [1 ]
Liu, Yue-Peng [1 ]
Huang, Zhi-Jiang [1 ]
Zhang, Yan-Kai [1 ]
Song, Xue-Jun [1 ]
机构
[1] Parker Univ, Res Inst, Dept Neurobiol, Dallas, TX 75229 USA
[2] Nanjing Univ, State Key Lab Pharmaceut Biotechnol, Nanjing 210008, Jiangsu, Peoples R China
基金
美国国家卫生研究院;
关键词
Nerve injury; Spinal cord; Cromakalim; Connexin; 43; Carbenoxolone; SATELLITE GLIAL-CELLS; PROTEIN CONNEXIN-43; PHORBOL ESTER; SRC; PHOSPHORYLATION; HYPERALGESIA; COMMUNICATION; CONTRIBUTES; ACTIVATION; GANGLION;
D O I
10.1016/j.pain.2011.08.003
中图分类号
R614 [麻醉学];
学科分类号
100217 ;
摘要
Adenosine triphosphate-sensitive potassium (K-ATP) channels are suggested to be involved in pathogenesis of neuropathic pain, but remain underinvestigated in primary afferents and in the spinal cord. We examined alterations of K-ATP channels in rat spinal cord and tested whether and how they could contribute to neuropathic pain. The results showed that protein expression for K-ATP channel subunits SUR1, SUR2, and Kir6.1, but not Kir6.2, were significantly downregulated and associated with thermal hyperalgesia and mechanical allodynia after sciatic nerve injury. Spinal administration of a K-ATP channel opener cromakalim (CRO, 5, 10, and 20 mu g, respectively) prevented or suppressed, in a dose-dependent manner, the hyperalgesia and allodynia. Nerve injury also significantly increased expression and phosphorylation of connexin 43, an astroglial gap junction protein. Such an increase of phosphorylation of connexin 43 was inhibited by CRO treatment. Furthermore, preadministration of an astroglial gap junction decoupler carbenoxolone (10 mu g) completely reversed the inhibitory effects of CRO treatment on the hyperalgesia and allodynia and phosphorylation of NR1 and NR2B receptors and the subsequent activation of Ca2+-dependent signals Ca2+/calmodulin-dependent kinase II and cyclic adenosine monophosphate (cAMP) response element binding protein. These findings suggest that nerve injury-induced downregulation of the K-ATP channels in the spinal cord may interrupt the astroglial gap junctional function and contribute to neuropathic pain, thus the K-ATP channels opener can reduce neuropathic pain probably partly via regulating the astroglial gap junctions. This study may provide a new strategy for treating neuropathic pain using K-ATP channel openers in the clinic. (C) 2011 International Association for the Study of Pain. Published by Elsevier B. V. All rights reserved.
引用
收藏
页码:2605 / 2615
页数:11
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