title: MeCP2 repression of G9a in regulation of pain and morphine reward.
abstract: Opioids are commonly used for pain relief, but their strong rewarding effects drive opioid misuse and abuse. How pain affects the liability of opioid abuse is unknown at present. In this study, we identified an epigenetic regulating cascade activated by both pain and the opioid morphine. Both persistent pain and repeated morphine upregulated the transcriptional regulator MeCP2 in mouse central nucleus of the amygdala (CeA). Chromatin immunoprecipitation analysis revealed that MeCP2 bound to and repressed the transcriptional repressor histone dimethyltransferase G9a, reducing G9a-catalyzed repressive mark H3K9me2 in CeA. Repression of G9a activity increased expression of brain-derived neurotrophic factor (BDNF). Behaviorally, persistent inflammatory pain increased the sensitivity to acquiring morphine-induced, reward-related behavior of conditioned place preference in mice. Local viral vector-mediated MeCP2 overexpression, Cre-induced G9a knockdown, and CeA application of BDNF mimicked, whereas MeCP2 knockdown inhibited, the pain effect. These results suggest that MeCP2 directly represses G9a as a shared mechanism in central amygdala for regulation of emotional responses to pain and opioid reward, and for their behavioral interaction.
authors.affiliation: Department of Anesthesiology and Pain Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, Key Laboratory of Brain Functions and Diseases, School of Life Science, University of Science and Technology of China, Hefei, Anhui 230027, China, and.
authors.forename: Zhi
authors.identifier: http://orcid.org/0000-0002-4205-3181
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Brain Functions and Diseases, School of Life Science, University of Science and Technology of China, Hefei, Anhui 230027, China, and.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Tao
authors.affiliation: Department of Anesthesiology and Pain Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Hou
authors.affiliation: Department of Anesthesiology and Pain Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Kenny
authors.affiliation: Department of Anesthesiology and Pain Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, zzpan@mdanderson.org.
authors.forename: Zhizhong Z
authors.initials: ZZ
authors.lastname: Pan
mesh_terms: D000679:Amygdala / Q000503:physiopathology*; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D059350:Chronic Pain / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology*; D003214:Conditioning, Classical / Q000502:physiology; D003433:Crosses, Genetic; D004198:Disease Susceptibility; D015536:Down-Regulation; D004644:Emotions / Q000502:physiology; D044127:Epigenesis, Genetic; D005106:Exploratory Behavior / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D005822:Genetic Vectors; D011495:Histone-Lysine N-Methyltransferase / Q000502:physiology*; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D009021:Morphine Dependence / Q000209:etiology / Q000523:psychology; D009294:Narcotics / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012054:Reinforcement, Psychology; D012201:Reward; D019076:Transgenes
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D009294:Narcotics; D009419:Nerve Tissue Proteins; D011993:Recombinant Fusion Proteins; D009020:Morphine; C533711:G9a protein, mouse; D011495:Histone-Lysine N-Methyltransferase
keywords: G9a; MeCP2; opioid; pain; reward