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.
Highlights
Neuropathic pain, affecting approximately 6.9–10% of the global world population, is a major source of suffering and disability, leading to a substantial healthcare costs and lost productivity (Cooper et al, 2017)
We revealed that the hypermethylated Oprm1 gene promoter could recruit methyl-CpG binding protein 2 (MeCP2) as well as HDAC1 after nerve injury, decreasing acetylation of the Oprm1 gene promoter region, resulting in the decreased expression of mu opioid receptor (MOR) in the dorsal root ganglion (DRG)
We demonstrated that peripheral nerve injury led to increases of MeCP2 and HDAC1 expression in injured DRG
Summary
Neuropathic pain, affecting approximately 6.9–10% of the global world population, is a major source of suffering and disability, leading to a substantial healthcare costs and lost productivity (Cooper et al, 2017). Neuropathic pain can be categorized into 2 main subgroups: (1) chronic pain with neuropathic characteristics and (2) neuropathic pain associated with a specific condition, MeCP2 Regulates MOR in DRG including postherpetic neuralgia, trigeminal neuralgia, painful diabetic peripheral neuropathy, and glossopharyngeal neuralgia (van Hecke et al, 2014). Despite their risks, opioids, such as morphine, are the main treatment option for neuropathic pain, but have limited effectiveness in patients with this debilitating disorder (Fields, 2004; Cooper et al, 2017; Els et al, 2017; Martinez-Navarro et al, 2018). We revealed that the hypermethylated Oprm gene promoter could recruit MeCP2 as well as HDAC1 after nerve injury, decreasing acetylation of the Oprm gene promoter region, resulting in the decreased expression of MOR in the DRG
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