Increased Methylation of the MOR Gene Proximal Promoter in Primary Sensory Neurons Plays a Crucial Role in the Decreased Analgesic Effect of Opioids in Neuropathic Pain

• Published in: Molecular pain 2014-08, Vol.10 (1), p.51-51
• Main Authors: Zhou, Xue-Long, Yu, Li-Na, Wang, Yin, Tang, Li-Hui, Peng, Yu-Nan, Cao, Jun-Li, Yan, Min
• Format: Article
• Language: English
• Subjects: Analgesia; Analgesics; Animals; Azacitidine - analogs & derivatives; Azacitidine - pharmacology; Azacytidine; Cell Line, Tumor; CpG Islands - drug effects; Disease Models, Animal; DNA methylation; Dorsal root ganglia; Dose-Response Relationship, Drug; Enzyme Inhibitors - pharmacology; Ganglia, Spinal - cytology; Gene expression; Gene Expression Regulation - drug effects; Hyperalgesia - drug therapy; Medical research; Methylation; Mice; Molecular modelling; Morphine; Morphine - administration & dosage; mRNA; Narcotics; Neuralgia - drug therapy; Neuralgia - metabolism; Neuralgia - pathology; Neuroblastoma - metabolism; Neuroblastoma - pathology; Opioid receptors (type mu); Pain management; Pain Measurement; Pain perception; Pain Threshold - drug effects; Peripheral nerves; Peripheral neuropathy; Plasmids; Promoter Regions, Genetic - drug effects; Promoter Regions, Genetic - physiology; Receptors, Opioid, mu - genetics; Receptors, Opioid, mu - metabolism; Sensory neurons; Sensory Receptor Cells - drug effects; Sensory Receptor Cells - metabolism; Spinal cord; Spinal Cord - drug effects; Spinal Cord - metabolism
• ISSN: 1744-8069; 1744-8069
• DOI: 10.1186/1744-8069-10-51

Background: The analgesic potency of opioids is reduced in neuropathic pain. However, the molecular mechanism is not well understood. Results: The present study demonstrated that increased methylation of the Mu opioid receptor (MOR) gene proximal promoter (PP) in dorsal root ganglion (DRG) plays a crucial role in the decreased morphine analgesia. Subcutaneous (s.c.), intrathecal (i.t.) and intraplantar (i.pl.), not intracerebroventricular (i.c.v.) injection of morphine, the potency of morphine analgesia was significantly reduced in nerve-injured mice compared with control sham-operated mice. After peripheral nerve injury, we observed a decreased expression of MOR protein and mRNA, accompanied by an increased methylation status of MOR gene PP, in DRG. However, peripheral nerve injury could not induce a decreased expression of MOR mRNA in the spinal cord. Treatment with 5-aza-2′-deoxycytidine (5-aza-dC), inhibited the increased methylation of MOR gene PP and prevented the decreased expression of MOR in DRG, thereby improved systemic, spinal and periphery morphine analgesia. Conclusions: Altogether, our results demonstrate that increased methylation of the MOR gene PP in DRG is required for the decreased morphine analgesia in neuropathic pain.