DNMT3a methylation in neuropathic pain
Authors Shao CJ, Gao Y, Jin D, Xu X, Tan SY, Yu H, Zhao QX, Zhao L, Wang WS, Wang DQ
Received 19 December 2016
Accepted for publication 24 July 2017
Published 18 September 2017 Volume 2017:10 Pages 2253—2262
Checked for plagiarism Yes
Review by Single-blind
Peer reviewers approved by Dr Colin Mak
Peer reviewer comments 2
Editor who approved publication: Dr Michael E Schatman
Cuijie Shao, Yong Gao, Dan Jin, Xin Xu, Shuying Tan, Hui Yu, Qingxiang Zhao, Li Zhao, Wansheng Wang, Deqiang Wang
Department of Pain, Binzhou Medical University Hospital, Binzhou, China
Background: Mu opioid receptor (MOR) plays a crucial role in mediating analgesic effects of opioids and is closely associated with the pathologies of neuropathic pain. Previous studies have reported that peripheral nerve injury downregulates MOR expression, but the epigenetic mechanisms remain unknown.
Objective: Therefore, we investigated DNA methyltransferase3a (DNMT3a) expression or methylation changes within MOR promoter in the spinal cord in a neuropathic pain induced by a chronic constriction injury (CCI) mouse model and further determined whether these injury-associated changes are reversible by pharmacological interventions.
Methods: A CCI mouse model was established and tissue specimens of lumbar spinal cords were collected. The nociception threshold was evaluated by a Model Heated 400 Base. DNMT3a and MOR mRNA and protein level were detected by real-time-polymerase chain reaction and Western blot, respectively. Methylation of DNMT3a gene was measured by methylation-specific PCR.
Results: Our data showed that chronic nerve injury led to a significant upregulation of DNMT3a expression that was associated with increased methylation of MOR gene promoter and decreased MOR protein expression in the spinal cord. Inhibition of DNMT3a catalytic activity with DNMT inhibitor RG108 significantly blocked the increase in methylation of the MOR promoter, and then upregulated MOR expression and attenuated thermal hyperalgesia in neuropathic pain mice.
Conclusion: This study demonstrates that an increase of DNMT3a expression and MOR methylation epigenetically play an important role in neuropathic pain. Targeting DNMT3a to the promoter of MOR gene by DNMT inhibitor may be a promising approach to the development of new neuropathic pain therapy.
Keywords: DNMT3A, pain, MOR, RG108, neuropathic pain
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