神经性疼痛条件下初级感觉神经元中Oprm1基因的MeCP2表观遗传沉默

2021年11月，杭州浙江大学医学院第二附属医院麻醉科；湖州市**人民医院麻醉科；杭州余杭**人民医院麻醉科(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老师研究团队在《Frontiers in Neuroscience》上发表论文：

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

“神经性疼痛条件下初级感觉神经元中Oprm1基因的MeCP2表观遗传沉默”

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：

阿片类药物是神经性疼痛药物治疗的最后选择，但其抗伤害感受作用有限。周围神经系统中mu阿片受体(MOR)表达的减少可能与此有关。在这里，我们发现神经损伤诱导Oprm1基因启动子的超甲基化和甲基- cpg结合蛋白2 (MeCP2)在损伤的背根神经节(DRG)中的表达增加。DRG中MOR的下调与MeCP2的增加密切相关，MeCP2是一种表观遗传抑制因子，可以招募HDAC1并结合到Oprm1基因启动子的甲基化区域。MeCP2敲低可以恢复损伤DRG中MOR的表达，增强吗啡的镇痛作用，而鞘内注入病毒载体介导的MeCP2足以模拟这种增加，从而降低DRG中的MOR。此外，HDAC抑制剂亚甲基苯胺羟肟酸抑制HDAC1也能阻止神经性疼痛小鼠DRG的MOR降低，从而增强吗啡的镇痛作用。机制上，上调MeCP2促进高水平的HDCA1与Oprm1基因启动子的高甲基化区域结合，降低Oprm1基因启动子乙酰化的组蛋白H3 (acH3)水平，并减弱受损DRG中Oprm1的转录。因此，上调Oprm1基因启动子位点的MeCP2和HDAC1，负向调节损伤DRG中MOR的表达，减轻阿片类药物的镇痛作用。因此，靶向MeCP2/HDAC1可能为提高阿片类药物在临床中的治疗效果提供新的解决方案。

该论文中，293T细胞的体外培养是使用Ausbian特级胎牛血清完成的。欲了解或购买Ausbian特级胎牛血清可以联系北京缔一生物400-166-8600.