Epigenetic modification of spinal miR-219 expression regulates chronic inflammation pain by targeting CaMKIIγ.

Abstract

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 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.

• Authors: 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, Jun-Li Cao
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 34 Issue 29 Pg. 9476-83 (Jul 16 2014) ISSN: 1529-2401 [Electronic] United States
• PMID: 25031391 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 the authors 0270-6474/14/349476-08$15.00/0.

Chemical References

• MIRN219 microRNA, human
• MicroRNAs
• RNA, Small Interfering
• Freund's Adjuvant
• Calcium-Calmodulin-Dependent Protein Kinase Type 2

Topics

• Animals
• Calcium-Calmodulin-Dependent Protein Kinase Type 2 (genetics, metabolism)
• Chronic Pain (etiology, metabolism, pathology)
• CpG Islands (genetics)
• Disease Models, Animal
• Epigenesis, Genetic (drug effects, genetics)
• Freund's Adjuvant (adverse effects)
• Gene Expression Regulation
• HEK293 Cells
• Humans
• Inflammation (chemically induced, complications)
• Male
• Mice
• Mice, Inbred Strains
• MicroRNAs (genetics, metabolism)
• Neurons (drug effects)
• Pain Measurement
• RNA, Small Interfering (pharmacology)
• Spinal Cord (metabolism, pathology)
• Transduction, Genetic