神經(jīng)性疼痛條件下初級(jí)感覺(jué)神經(jīng)元中Oprm1基因的MeCP2表觀遺傳沉默

2021年11月，杭州浙江大學(xué)醫(yī)學(xué)院第二附屬醫(yī)院麻醉科；湖州市**人民醫(yī)院麻醉科；杭州余杭**人民醫(yī)院麻醉科(Department of Anesthesiology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China；Department of Anesthesiology, The First People’s Hospital of Huzhou, Huzhou, China；Department of Anesthesiology,Yuhang First People’s Hospital, Hangzhou, China) Min Yan老師研究團(tuán)隊(duì)在《Frontiers in Neuroscience》上發(fā)表論文：

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

“神經(jīng)性疼痛條件下初級(jí)感覺(jué)神經(jīng)元中Oprm1基因的MeCP2表觀遺傳沉默”

Abstract：

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.

摘要：

阿片類(lèi)藥物是神經(jīng)性疼痛藥物治療的最后選擇，但其抗傷害感受作用有限。周?chē)窠?jīng)系統(tǒng)中mu阿片受體(MOR)表達(dá)的減少可能與此有關(guān)。在這里，我們發(fā)現(xiàn)神經(jīng)損傷誘導(dǎo)Oprm1基因啟動(dòng)子的超甲基化和甲基- cpg結(jié)合蛋白2 (MeCP2)在損傷的背根神經(jīng)節(jié)(DRG)中的表達(dá)增加。DRG中MOR的下調(diào)與MeCP2的增加密切相關(guān)，MeCP2是一種表觀遺傳抑制因子，可以招募HDAC1并結(jié)合到Oprm1基因啟動(dòng)子的甲基化區(qū)域。MeCP2敲低可以恢復(fù)損傷DRG中MOR的表達(dá)，增強(qiáng)嗎啡的鎮(zhèn)痛作用，而鞘內(nèi)注入病毒載體介導(dǎo)的MeCP2足以模擬這種增加，從而降低DRG中的MOR。此外，HDAC抑制劑亞甲基苯胺羥肟酸抑制HDAC1也能阻止神經(jīng)性疼痛小鼠DRG的MOR降低，從而增強(qiáng)嗎啡的鎮(zhèn)痛作用。機(jī)制上，上調(diào)MeCP2促進(jìn)高水平的HDCA1與Oprm1基因啟動(dòng)子的高甲基化區(qū)域結(jié)合，降低Oprm1基因啟動(dòng)子乙酰化的組蛋白H3 (acH3)水平，并減弱受損DRG中Oprm1的轉(zhuǎn)錄。因此，上調(diào)Oprm1基因啟動(dòng)子位點(diǎn)的MeCP2和HDAC1，負(fù)向調(diào)節(jié)損傷DRG中MOR的表達(dá)，減輕阿片類(lèi)藥物的鎮(zhèn)痛作用。因此，靶向MeCP2/HDAC1可能為提高阿片類(lèi)藥物在臨床中的治療效果提供新的解決方案。

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