MeCP2 Epigenetic Silencing of Oprm1 Gene in Primary Sensory Neurons Under Neuropathic Pain Conditions

Opioids are the last option for the pharmacological treatment of neuropathic pain, but their antinociceptive effects are limited. Decreased mu opioid receptor (MOR) expression in the peripheral nervous system may contribute to this. Here, we showed that nerve injury induced hypermethylation of the O...

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Autores principales:	Na Sun, Lina Yu, Yibo Gao, Longfei Ma, Jinxuan Ren, Ying Liu, Dave Schwinn Gao, Chen Xie, Ying Wu, Lieju Wang, Juncong Hong, Min Yan
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	morphine neuropathic pain MOR DNA methylation histone acetylation Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
Acceso en línea:	https://doaj.org/article/d8bbc4da68054601ab5b8fa8e9e4f113
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spelling	oai:doaj.org-article:d8bbc4da68054601ab5b8fa8e9e4f1132021-11-05T10:37:02ZMeCP2 Epigenetic Silencing of Oprm1 Gene in Primary Sensory Neurons Under Neuropathic Pain Conditions1662-453X10.3389/fnins.2021.743207https://doaj.org/article/d8bbc4da68054601ab5b8fa8e9e4f1132021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fnins.2021.743207/fullhttps://doaj.org/toc/1662-453XOpioids are the last option for the pharmacological treatment of neuropathic pain, but their antinociceptive effects are limited. Decreased mu opioid receptor (MOR) expression in the peripheral nervous system may contribute to this. Here, we showed that nerve injury induced hypermethylation of the Oprm1 gene promoter and an increased expression of methyl-CpG binding protein 2 (MeCP2) in injured dorsal root ganglion (DRG). The downregulation of MOR in the DRG is closely related to the augmentation of MeCP2, an epigenetic repressor, which could recruit HDAC1 and bind to the methylated regions of the Oprm1 gene promoter. MeCP2 knockdown restored the expression of MOR in injured DRG and enhanced the analgesic effect of morphine, while the mimicking of this increase via the intrathecal infusion of viral vector-mediated MeCP2 was sufficient to reduce MOR in the DRG. Moreover, HDAC1 inhibition with suberoylanilide hydroxamic acid, an HDAC inhibitor, also prevented MOR reduction in the DRG of neuropathic pain mice, contributing to the augmentation of morphine analgesia effects. Mechanistically, upregulated MeCP2 promotes the binding of a high level of HDCA1 to hypermethylated regions of the Oprm1 gene promoter, reduces the acetylation of histone H3 (acH3) levels of the Oprm1 gene promoter, and attenuates Oprm1 transcription in injured DRG. Thus, upregulated MeCP2 and HDAC1 in Oprm1 gene promoter sites, negatively regulates MOR expression in injured DRG, mitigating the analgesic effect of the opioids. Targeting MeCP2/HDAC1 may thus provide a new solution for improving the therapeutic effect of opioids in a clinical setting.Na SunLina YuYibo GaoLongfei MaJinxuan RenYing LiuDave Schwinn GaoChen XieYing WuLieju WangJuncong HongMin YanFrontiers Media S.A.articlemorphineneuropathic painMORDNA methylationhistone acetylationNeurosciences. Biological psychiatry. NeuropsychiatryRC321-571ENFrontiers in Neuroscience, Vol 15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	morphine neuropathic pain MOR DNA methylation histone acetylation Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
spellingShingle	morphine neuropathic pain MOR DNA methylation histone acetylation Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Na Sun Lina Yu Yibo Gao Longfei Ma Jinxuan Ren Ying Liu Dave Schwinn Gao Chen Xie Ying Wu Lieju Wang Juncong Hong Min Yan MeCP2 Epigenetic Silencing of Oprm1 Gene in Primary Sensory Neurons Under Neuropathic Pain Conditions
description	Opioids are the last option for the pharmacological treatment of neuropathic pain, but their antinociceptive effects are limited. Decreased mu opioid receptor (MOR) expression in the peripheral nervous system may contribute to this. Here, we showed that nerve injury induced hypermethylation of the Oprm1 gene promoter and an increased expression of methyl-CpG binding protein 2 (MeCP2) in injured dorsal root ganglion (DRG). The downregulation of MOR in the DRG is closely related to the augmentation of MeCP2, an epigenetic repressor, which could recruit HDAC1 and bind to the methylated regions of the Oprm1 gene promoter. MeCP2 knockdown restored the expression of MOR in injured DRG and enhanced the analgesic effect of morphine, while the mimicking of this increase via the intrathecal infusion of viral vector-mediated MeCP2 was sufficient to reduce MOR in the DRG. Moreover, HDAC1 inhibition with suberoylanilide hydroxamic acid, an HDAC inhibitor, also prevented MOR reduction in the DRG of neuropathic pain mice, contributing to the augmentation of morphine analgesia effects. Mechanistically, upregulated MeCP2 promotes the binding of a high level of HDCA1 to hypermethylated regions of the Oprm1 gene promoter, reduces the acetylation of histone H3 (acH3) levels of the Oprm1 gene promoter, and attenuates Oprm1 transcription in injured DRG. Thus, upregulated MeCP2 and HDAC1 in Oprm1 gene promoter sites, negatively regulates MOR expression in injured DRG, mitigating the analgesic effect of the opioids. Targeting MeCP2/HDAC1 may thus provide a new solution for improving the therapeutic effect of opioids in a clinical setting.
format	article
author	Na Sun Lina Yu Yibo Gao Longfei Ma Jinxuan Ren Ying Liu Dave Schwinn Gao Chen Xie Ying Wu Lieju Wang Juncong Hong Min Yan
author_facet	Na Sun Lina Yu Yibo Gao Longfei Ma Jinxuan Ren Ying Liu Dave Schwinn Gao Chen Xie Ying Wu Lieju Wang Juncong Hong Min Yan
author_sort	Na Sun
title	MeCP2 Epigenetic Silencing of Oprm1 Gene in Primary Sensory Neurons Under Neuropathic Pain Conditions
title_short	MeCP2 Epigenetic Silencing of Oprm1 Gene in Primary Sensory Neurons Under Neuropathic Pain Conditions
title_full	MeCP2 Epigenetic Silencing of Oprm1 Gene in Primary Sensory Neurons Under Neuropathic Pain Conditions
title_fullStr	MeCP2 Epigenetic Silencing of Oprm1 Gene in Primary Sensory Neurons Under Neuropathic Pain Conditions
title_full_unstemmed	MeCP2 Epigenetic Silencing of Oprm1 Gene in Primary Sensory Neurons Under Neuropathic Pain Conditions
title_sort	mecp2 epigenetic silencing of oprm1 gene in primary sensory neurons under neuropathic pain conditions
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/d8bbc4da68054601ab5b8fa8e9e4f113
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MeCP2 Epigenetic Silencing of Oprm1 Gene in Primary Sensory Neurons Under Neuropathic Pain Conditions

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