title: Reopening of ATP-sensitive potassium channels reduces neuropathic pain and regulates astroglial gap junctions in the rat spinal cord.
abstract: 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 μg, 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 μg) 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 Ca(2+)-dependent signals Ca(2+)/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.
authors: Department of Neurobiology, Parker University Research Institute, Dallas, TX, USA State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, Jiangsu, China.
authors: Xue-Feng
authors: XF
authors: Wu
authors: Wen-Tao
authors: WT
authors: Liu
authors: Yue-Peng
authors: YP
authors: Liu
authors: Zhi-Jiang
authors: ZJ
authors: Huang
authors: Yan-Kai
authors: YK
authors: Zhang
authors: Xue-Jun
authors: XJ
authors: Song
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000009:adverse effects / Q000502:physiology; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000502:physiology; D019806:Cromakalim / Q000494:pharmacology*; D017629:Gap Junctions / Q000187:drug effects / Q000502:physiology; D006930:Hyperalgesia / Q000503:physiopathology; D054086:KATP Channels / Q000819:agonists* / Q000502:physiology*; D008297:Male; D009437:Neuralgia / Q000188:drug therapy* / Q000503:physiopathology*; D024661:Potassium Channels, Inwardly Rectifying / Q000009:adverse effects / Q000819:agonists / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011955:Receptors, Drug / Q000502:physiology; D012585:Sciatica / Q000188:drug therapy / Q000503:physiopathology; D013116:Spinal Cord / Q000187:drug effects / Q000503:physiopathology*; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel
chemical_list: D018528:ATP-Binding Cassette Transporters; D019806:Cromakalim; D054086:KATP Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel; C577509:Abcc8 protein, rat; C577512:Abcc9 protein, rat; C092520:uK-ATP-1 potassium channel