title: G9a inhibits CREB-triggered expression of mu opioid receptor in primary sensory neurons following peripheral nerve injury.
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.
authors.affiliation: Department of Anesthesiology, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, USA.
authors.forename: Lingli
authors.initials: L
authors.lastname: Liang
authors.affiliation: Department of Anesthesiology, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, USA.|State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China.
authors.forename: Jian-Yuan
authors.initials: JY
authors.lastname: Zhao
authors.affiliation: Department of Anesthesiology, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, USA.
authors.forename: Xiyao
authors.initials: X
authors.lastname: Gu
authors.affiliation: Department of Anesthesiology, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, USA.
authors.forename: Shaogen
authors.initials: S
authors.lastname: Wu
authors.affiliation: Department of Anesthesiology, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Mo
authors.affiliation: Department of Anesthesiology, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Xiong
authors.affiliation: Department of Anesthesiology, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, USA.
authors.forename: Brianna
authors.initials: B
authors.lastname: Marie Lutz
authors.affiliation: Department of Anesthesiology, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Bekker
authors.affiliation: Department of Anesthesiology, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, USA yuanxiang.tao@njms.rutgers.edu.|Department of Cell Biology & Molecular Medicine, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, USA.|Department of Physiology, Pharmacology & Neuroscience, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, USA.
authors.forename: Yuan-Xiang
authors.initials: YX
authors.lastname: Tao
mesh_terms: D000818:Animals; D050882:CREB-Binding Protein / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D007839:Functional Laterality; D005727:Ganglia, Spinal / Q000473:pathology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D008139:Loperamide / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D009294:Narcotics / Q000494:pharmacology / Q000627:therapeutic use; D059348:Peripheral Nerve Injuries / Q000473:pathology*; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000235:genetics / Q000378:metabolism; D017465:Receptors, Opioid, delta / Q000235:genetics / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism*; D000094942:Nociceptin Receptor
chemical_list: C113762:Avil protein, mouse; C470381:DOR-1 protein, mouse; D008840:Microfilament Proteins; D009294:Narcotics; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D008139:Loperamide; C533711:G9a protein, mouse; D011495:Histone-Lysine N-Methyltransferase; D050882:CREB-Binding Protein; D000094942:Nociceptin Receptor
keywords: G9a; dorsal root ganglion; nerve injury; opioid receptor