G9a inhibits CREB-triggered expression of mu opioid receptor in primary sensory neurons following peripheral nerve injury

Mol Pain. 2016 Dec 7;12:1744806916682242. doi: 10.1177/1744806916682242. Print 2016.

Abstract

Neuropathic pain, a distressing and debilitating disorder, is still poorly managed in clinic. Opioids, like morphine, remain the mainstay of prescribed medications in the treatment of this disorder, but their analgesic effects are highly unsatisfactory in part due to nerve injury-induced reduction of opioid receptors in the first-order sensory neurons of dorsal root ganglia. G9a is a repressor of gene expression. We found that nerve injury-induced increases in G9a and its catalyzed repressive marker H3K9m2 are responsible for epigenetic silencing of Oprm1, Oprk1, and Oprd1 genes in the injured dorsal root ganglia. Blocking these increases rescued dorsal root ganglia Oprm1, Oprk1, and Oprd1 gene expression and morphine or loperamide analgesia and prevented the development of morphine or loperamide-induced analgesic tolerance under neuropathic pain conditions. Conversely, mimicking these increases reduced the expression of three opioid receptors and promoted the mu opioid receptor-gated release of primary afferent neurotransmitters. Mechanistically, nerve injury-induced increases in the binding activity of G9a and H3K9me2 to the Oprm1 gene were associated with the reduced binding of cyclic AMP response element binding protein to the Oprm1 gene. These findings suggest that G9a participates in the nerve injury-induced reduction of the Oprm1 gene likely through G9a-triggered blockage in the access of cyclic AMP response element binding protein to this gene.

Keywords: G9a; dorsal root ganglion; nerve injury; opioid receptor.

MeSH terms

  • Animals
  • CREB-Binding Protein / genetics
  • CREB-Binding Protein / metabolism*
  • Disease Models, Animal
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / pharmacology
  • Functional Laterality
  • Ganglia, Spinal / pathology*
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / metabolism*
  • Loperamide / pharmacology
  • Membrane Potentials / drug effects
  • Membrane Potentials / genetics
  • Mice
  • Mice, Inbred C57BL
  • Microfilament Proteins / genetics
  • Microfilament Proteins / metabolism
  • Narcotics / pharmacology
  • Narcotics / therapeutic use
  • Peripheral Nerve Injuries / pathology*
  • Rats, Sprague-Dawley
  • Receptors, Opioid / genetics
  • Receptors, Opioid / metabolism
  • Receptors, Opioid, delta / genetics
  • Receptors, Opioid, delta / metabolism
  • Receptors, Opioid, mu / metabolism*
  • Sensory Receptor Cells / drug effects
  • Sensory Receptor Cells / metabolism*

Substances

  • Avil protein, mouse
  • DOR-1 protein, mouse
  • Microfilament Proteins
  • Narcotics
  • Receptors, Opioid
  • Receptors, Opioid, delta
  • Receptors, Opioid, mu
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
  • Loperamide
  • nociceptin receptor
  • G9a protein, mouse
  • Histone-Lysine N-Methyltransferase
  • CREB-Binding Protein