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Epigenetic modification of spinal miR-219 expression regulates chronic inflammation pain by targeting CaMKIIγ
Zhiqiang Pan1, Li-Jiao Zhu1, Yan-Qiang Li1
1Jiangsu 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.
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.
Insights
Chronic inflammatory pain in mice involves decreased microRNA-219 (miR-219) in spinal neurons. Restoring miR-219 alleviates pain by targeting CaMKIIγ, suggesting epigenetic regulation of chronic pain.
Area of Science:
- Neuroscience
- Molecular Biology
- Epigenetics
Background:
- MicroRNA (miRNA)-mediated gene expression is implicated in chronic pain.
- The precise regulatory mechanisms, particularly epigenetic modifications, remain largely unelucidated.
Purpose of the Study:
- To investigate the role of microRNA-219 (miR-219) in chronic inflammatory pain.
- To elucidate the functional regulatory mechanism of miR-219 in the spinal cord.
Main Methods:
- Complete Freund's adjuvant (CFA) model of chronic inflammatory pain in mice.
- Spinal cord tissue analysis for miR-219 and CaMKIIγ expression.
- In vivo manipulation of miR-219 levels and CaMKIIγ knockdown.
- Bisulfite sequencing for promoter methylation analysis.
- Administration of a demethylation agent (5'-aza-2'-deoxycytidine).
Main Results:
- CFA-induced pain significantly reduced spinal miR-219 expression and increased its target, CaMKIIγ.
- Overexpression of miR-219 reversed pain behaviors, neuronal sensitization, and CaMKIIγ levels.
- Downregulation of miR-219 induced pain behaviors and increased p-NMDAR1, which was reversed by CaMKIIγ knockdown.
- CFA induced hypermethylation of the miR-219 promoter.
- Demethylation treatment attenuated pain and increased miR-219 while decreasing CaMKIIγ.
Conclusions:
- Epigenetic modification, specifically methylation of the miR-219 promoter, regulates chronic inflammatory pain.
- Spinal miR-219 targets CaMKIIγ to modulate pain signaling.
- miR-219 represents a potential therapeutic target for chronic inflammatory pain.
