• Ning Shen, Li-Qiu Mo, Fen Hu, Pei-Xi Chen, Rui-Xian Guo, and Jian-Qiang Feng.
• Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
• CNS Neurosci Ther. 2014 Aug 1;20(8):728-36.

AimsConnexin 43 (Cx43) has been reported to be involved in neuropathic pain, but whether it contributes to morphine antinociceptive tolerance remains unknown. The present study investigated the role of spinal Cx43 in the development of morphine tolerance and its mechanisms in rats.MethodsMorphine tolerance was induced by intrathecal (i.t.) administration of morphine (15 μg) daily for seven consecutive days. The analgesia effect was assessed by hot-water tail-flick test. Expression of proteins was detected by Western blot and immunohistochemistry assay.ResultsChronic morphine markedly increased the expression of spinal Cx43. Gap26, a specific Cx43 mimic peptide, attenuated not only morphine antinociceptive tolerance, but also the up-regulation of spinal Cx43 expression, the activation of astrocytes, and N-methyl-D-aspartic acid (NMDA) receptors (NR1 and NR2B subunits), as well as the decreased GLT-1 expression induced by chronic morphine. MK-801, a noncompetitive NMDA receptors antagonist, suppressed the chronic morphine-induced spinal Cx43 up-regulation, astrocytes activation and decline of GLT-1 expression.ConclusionsThe spinal astrocytic Cx43 contributes to the development of morphine antinociceptive tolerance by activating astrocytes and NMDA receptors, and inhibiting GLT-1 expression. We also demonstrate that the role of interaction between the spinal astrocytic Cx43 and neuronal NMDA receptors is important in morphine tolerant rats.© 2014 John Wiley & Sons Ltd.

37 keywords...

hide…