1. Nerve injury–induced epigenetic silencing of opioid receptors controlled by DNMT3a in primary afferent neurons
- Author
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Weixiang Guo, Alex Bekker, Shaogen Wu, Xinyu Zhao, Jun Zhang, Lingli Liang, Linlin Sun, Xiyao Gu, Kai Mo, Jian Feng, Yuan Xiang Tao, Eric J. Nestler, and Jian-Yuan Zhao
- Subjects
Male ,0301 basic medicine ,Pharmacology ,κ-opioid receptor ,Article ,DNA Methyltransferase 3A ,Epigenesis, Genetic ,Rats, Sprague-Dawley ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Species Specificity ,Dorsal root ganglion ,Peripheral Nerve Injuries ,Animals ,Medicine ,Gene silencing ,DNA (Cytosine-5-)-Methyltransferases ,Gene Silencing ,Neurons, Afferent ,Mice, Knockout ,business.industry ,Nerve injury ,Rats ,Analgesics, Opioid ,Mice, Inbred C57BL ,030104 developmental biology ,Anesthesiology and Pain Medicine ,medicine.anatomical_structure ,nervous system ,Neurology ,Opioid ,Receptors, Opioid ,Neuropathic pain ,DNA methylation ,Neurology (clinical) ,μ-opioid receptor ,medicine.symptom ,business ,Neuroscience ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Opioids are the gold standard for pharmacological treatment of neuropathic pain, but their analgesic effects are unsatisfactory in part due to nerve injury-induced downregulation of opioid receptors in dorsal root ganglia (DRG) neurons. How nerve injury drives such downregulation remains elusive. DNA methyltransferase-(DNMT-) triggered DNA methylation represses gene expression. We show here that blocking the nerve injury-induced increase in DRG DNMT3a (a de novo DNMT) rescued the expression of Oprm1 and Oprk1 mRNAs and their respective encoding mu opioid receptor (MOR) and kappa opioid receptor (KOR) proteins in the injured DRG. Blocking this increase also prevented the nerve injury-induced increase in DNA methylation in the promoter and 5′-untranslated region of the Oprm1 gene in the injured DRG, restored morphine or loperamide (a peripheral acting MOR preferring agonist) analgesic effects, and attenuated the development of their analgesic tolerance under neuropathic pain conditions. Mimicking this increase reduced the expression of Oprm1 and Oprk1 mRNAs and their coding MOR and KOR in DRG and augmented MOR-gated neurotransmitter release from the primary afferents. Mechanistically, DNMT3a regulation of Oprm1 gene expression required the methyl-CpG-binding protein 1, MBD1, as MBD1 knockout resulted in the decreased binding of DNMT3a to the Oprm1 gene promoter and blocked the DNMT3a-triggered repression of Oprm1 gene expression in DRG neurons. These data suggest that DNMT3a is required for nerve injury-induced and MBD1-mediated epigenetic silencing of the MOR and KOR in the injured DRG. DNMT3a inhibition may serve as a promising adjuvant therapy for opioid use in neuropathic pain management.
- Published
- 2017