• Zhiqiang Pan, Li-Jiao Zhu, Yan-Qiang Li, Ling-Yun Hao, Cui Yin, Jun-Xia Yang, Yubai Guo, Song Zhang, Lu Hua, Zhou-Ya Xue, Hongxing Zhang, and Jun-Li Cao.
• Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou 221002, China, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical College, Xuzhou 221002, China, and.
• J. Neurosci. 2014 Jul 16;34(29):9476-83.

AbstractEmerging evidence has shown that miRNA-mediated gene expression modulation contributes to chronic pain, but its functional regulatory mechanism remains unknown. Here, we found that complete Freund's adjuvant (CFA)-induced chronic inflammation pain significantly reduced miRNA-219 (miR-219) expression in mice spinal neurons. Furthermore, the expression of spinal CaMKIIγ, an experimentally validated target of miR-219, was increased in CFA mice. Overexpression of spinal miR-219 prevented and reversed thermal hyperalgesia and mechanical allodynia and spinal neuronal sensitization induced by CFA. Concurrently, increased expression of spinal CaMKIIγ was reversed by miR-219 overexpression. Downregulation of spinal miR-219 in naive mice induced pain-responsive behaviors and increased p-NMDAR1 expression, which could be inhibited by knockdown of CaMKIIγ. Bisulfite sequencing showed that CFA induced the hypermethylation of CpG islands in the miR-219 promoter. Treatment with demethylation agent 5'-aza-2'-deoxycytidine markedly attenuated pain behavior and spinal neuronal sensitization, which was accompanied with the increase of spinal miR-219 and decrease of CaMKIIγ expression. Together, we conclude that methylation-mediated epigenetic modification of spinal miR-219 expression regulates chronic inflammatory pain by targeting CaMKIIγ.Copyright © 2014 the authors 0270-6474/14/349476-08$15.00/0.

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