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

Mol Pain. 2014 Aug 13;10:51. doi: 10.1186/1744-8069-10-51.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Azacitidine / analogs & derivatives
  • Azacitidine / pharmacology
  • Cell Line, Tumor
  • CpG Islands / drug effects
  • Decitabine
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology
  • Ganglia, Spinal / cytology
  • Gene Expression Regulation / drug effects
  • Hyperalgesia / drug therapy
  • Methylation
  • Mice
  • Morphine / administration & dosage*
  • Neuralgia* / drug therapy
  • Neuralgia* / metabolism
  • Neuralgia* / pathology
  • Neuroblastoma / metabolism
  • Neuroblastoma / pathology
  • Pain Measurement
  • Pain Threshold / drug effects
  • Promoter Regions, Genetic / drug effects
  • Promoter Regions, Genetic / physiology*
  • Receptors, Opioid, mu / genetics*
  • Receptors, Opioid, mu / metabolism*
  • Sensory Receptor Cells / drug effects
  • Sensory Receptor Cells / metabolism*
  • Spinal Cord / drug effects
  • Spinal Cord / metabolism

Substances

  • Enzyme Inhibitors
  • Receptors, Opioid, mu
  • Morphine
  • Decitabine
  • Azacitidine