title: DNA Methylation Modulates Nociceptive Sensitization after Incision.
abstract: DNA methylation is a key epigenetic mechanism controlling DNA accessibility and gene expression. Blockade of DNA methylation can significantly affect pain behaviors implicated in neuropathic and inflammatory pain. However, the role of DNA methylation with regard to postoperative pain has not yet been explored. In this study we sought to investigate the role of DNA methylation in modulating incisional pain and identify possible targets under DNA methylation and contributing to incisional pain. DNA methyltranferase (DNMT) inhibitor 5-Aza-2'-deoxycytidine significantly reduced incision-induced mechanical allodynia and thermal sensitivity. Aza-2'-deoxycytidine also reduced hindpaw swelling after incision, suggesting an anti-inflammatory effect. Global DNA methylation and DNMT3b expression were increased in skin after incision, but none of DNMT1, DNMT3a or DNMT3b was altered in spinal cord or DRG. The expression of proopiomelanocortin Pomc encoding β-endorphin and Oprm1 encoding the mu-opioid receptor were upregulated peripherally after incision; moreover, Oprm1 expression was further increased under DNMT inhibitor treatment. Finally, local peripheral injection of the opioid receptor antagonist naloxone significantly exacerbated incision-induced mechanical hypersensitivity. These results suggest that DNA methylation is functionally relevant to incisional nociceptive sensitization, and that mu-opioid receptor signaling might be one methylation regulated pathway controlling sensitization after incision.
authors.affiliation: Department of Anesthesiology, Stanford University School of Medicine, Stanford, California, United States of America.|Department of Anesthesiology, Veterans Affairs Palo Alto Health Care System, Palo Alto, California, United States of America.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Anesthesiology, Stanford University School of Medicine, Stanford, California, United States of America.|Department of Anesthesiology, Veterans Affairs Palo Alto Health Care System, Palo Alto, California, United States of America.
authors.forename: Peyman
authors.initials: P
authors.lastname: Sahbaie
authors.affiliation: Department of Anesthesiology, Stanford University School of Medicine, Stanford, California, United States of America.|Department of Anesthesiology, Veterans Affairs Palo Alto Health Care System, Palo Alto, California, United States of America.
authors.forename: DeYong
authors.initials: D
authors.lastname: Liang
authors.affiliation: Department of Anesthesiology, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Wenwu
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Anesthesiology, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Xiaoyou
authors.initials: X
authors.lastname: Shi
authors.affiliation: Department of Anesthesiology, Stanford University School of Medicine, Stanford, California, United States of America.|Department of Anesthesiology, Veterans Affairs Palo Alto Health Care System, Palo Alto, California, United States of America.
authors.forename: Paige
authors.initials: P
authors.lastname: Kingery
authors.affiliation: Department of Anesthesiology, Stanford University School of Medicine, Stanford, California, United States of America.|Department of Anesthesiology, Veterans Affairs Palo Alto Health Care System, Palo Alto, California, United States of America.
authors.forename: J David
authors.initials: JD
authors.lastname: Clark
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D019175:DNA Methylation; D000077209:Decitabine; D004487:Edema / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation / Q000187:drug effects*; D006614:Hindlimb / Q000187:drug effects / Q000293:injuries / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D059225:Nociception / Q000187:drug effects*; D010147:Pain Measurement; D060888:Real-Time Polymerase Chain Reaction; D017450:Receptors, Opioid, mu / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D014950:Wounds, Penetrating / Q000188:drug therapy* / Q000235:genetics
chemical_list: D000964:Antimetabolites, Antineoplastic; C404943:Oprm protein, mouse; D017450:Receptors, Opioid, mu; D000077209:Decitabine; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619381:Dnmt1 protein, mouse; D001374:Azacitidine