期刊
JOURNAL OF NEUROSCIENCE
卷 34, 期 29, 页码 9476-9483出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.5346-13.2014
关键词
CaMKII gamma; epigenetics; microRNA; pain; spinal cord
资金
- National Natural Science Foundation of China [81070888, 81230025, 81271231]
- Natural Science Foundation of Jiangsu Education Department [11KJA320001]
- China Postdoctoral Science Foundation [2012M511322]
- Natural Science Foundation of Jiangsu Province [BK2011196]
- Qing Lan Project of Jiangsu
- Jiangsu Provincial Six Talent Summit Action Plans
- Priority Academic Program Development of Jiangsu Higher Education Institutions
Emerging 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 CaMKII gamma, 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 CaMKII gamma 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 CaMKII gamma. 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 CaMKII gamma expression. Together, we conclude that methylation-mediated epigenetic modification of spinal miR-219 expression regulates chronic inflammatory pain by targeting CaMKII gamma.
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