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DNMT3a methylation in neuropathic pain

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 unkno...

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Autores principales: Shao, Cuijie, Gao, Yong, Jin, Dan, Xu, Xin, Tan, Shuying, Yu, Hui, Zhao, Qingxiang, Zhao, Li, Wang, Wansheng, Wang, Deqiang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove Medical Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5609796/
https://www.ncbi.nlm.nih.gov/pubmed/29075135
http://dx.doi.org/10.2147/JPR.S130654
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author Shao, Cuijie
Gao, Yong
Jin, Dan
Xu, Xin
Tan, Shuying
Yu, Hui
Zhao, Qingxiang
Zhao, Li
Wang, Wansheng
Wang, Deqiang
author_facet Shao, Cuijie
Gao, Yong
Jin, Dan
Xu, Xin
Tan, Shuying
Yu, Hui
Zhao, Qingxiang
Zhao, Li
Wang, Wansheng
Wang, Deqiang
author_sort Shao, Cuijie
collection PubMed
description 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.
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spelling pubmed-56097962017-10-26 DNMT3a methylation in neuropathic pain Shao, Cuijie Gao, Yong Jin, Dan Xu, Xin Tan, Shuying Yu, Hui Zhao, Qingxiang Zhao, Li Wang, Wansheng Wang, Deqiang J Pain Res Original Research 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. Dove Medical Press 2017-09-18 /pmc/articles/PMC5609796/ /pubmed/29075135 http://dx.doi.org/10.2147/JPR.S130654 Text en © 2017 Shao et al. This work is published and licensed by Dove Medical Press Limited The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.
spellingShingle Original Research
Shao, Cuijie
Gao, Yong
Jin, Dan
Xu, Xin
Tan, Shuying
Yu, Hui
Zhao, Qingxiang
Zhao, Li
Wang, Wansheng
Wang, Deqiang
DNMT3a methylation in neuropathic pain
title DNMT3a methylation in neuropathic pain
title_full DNMT3a methylation in neuropathic pain
title_fullStr DNMT3a methylation in neuropathic pain
title_full_unstemmed DNMT3a methylation in neuropathic pain
title_short DNMT3a methylation in neuropathic pain
title_sort dnmt3a methylation in neuropathic pain
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5609796/
https://www.ncbi.nlm.nih.gov/pubmed/29075135
http://dx.doi.org/10.2147/JPR.S130654
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