title: Epigenetic regulation of spinal CXCR2 signaling in incisional hypersensitivity in mice.
abstract: BACKGROUND
  The regulation of gene expression in nociceptive pathways contributes to the induction and maintenance of pain sensitization. Histone acetylation is a key epigenetic mechanism controlling chromatin structure and gene expression. Chemokine CC motif receptor 2 (CXCR2) is a proinflammatory receptor implicated in neuropathic and inflammatory pain and is known to be regulated by histone acetylation in some settings. The authors sought to investigate the role of histone acetylation on spinal CXCR2 signaling after incision.
  
  
  METHODS
  Groups of 5-8 mice underwent hind paw incision. Suberoylanilide hydroxamic acid and anacardic acid were used to inhibit histone deacetylase and histone acetyltransferase, respectively. Behavioral measures of thermal and mechanical sensitization as well as hyperalgesic priming were used. Both message RNA quantification and chromatin immunoprecipitation analysis were used to study the regulation of CXCR2 and ligand expression. Finally, the selective CXCR2 antagonist SB225002 was administered intrathecally to reveal the function of spinal CXCR2 receptors after hind paw incision.
  
  
  RESULTS
  Suberoylanilide hydroxamic acid significantly exacerbated mechanical sensitization after incision. Conversely, anacardic acid reduced incisional sensitization and also attenuated incision-induced hyperalgesic priming. Overall, acetylated histone H3 at lysine 9 was increased in spinal cord tissues after incision, and enhanced association of acetylated histone H3 at lysine 9 with the promoter regions of CXCR2 and keratinocyte-derived chemokine (CXCL1) was observed as well. Blocking CXCR2 reversed mechanical hypersensitivity after hind paw incision.
  
  
  CONCLUSIONS
  Histone modification is an important epigenetic mechanism regulating incision-induced nociceptive sensitization. The spinal CXCR2 signaling pathway is one epigenetically regulated pathway controlling early and latent sensitization after incision.
authors.affiliation: * Postdoctoral Fellow, † Research Associate, ‡ Senior Research Scientist, # Professor, Department of Anesthesiology, Stanford University School of Medicine, Stanford, California, and Department of Anesthesiology, Veterans Affairs Palo Alto Health Care System, Palo Alto, California. § Senior Research Scientist, ‖ Research Assistant, Department of Anesthesiology, Stanford University School of Medicine. Received from the Anesthesia and Perioperative Medicine Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, California. Submitted for publication February 19, 2013. Accepted for publication May 17, 2013. The work was supported by NIH award GM079126 (Bethesda, Maryland) and VA Merit Review award 5I01BX000881 (Washington, D.C.). The authors declare no competing interests. Some findings included in this article were presented in abstract form at the annual meeting of the Society for Neuroscience, October 13-17, 2012, New Orleans, Louisiana.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Sun
authors.forename: Peyman
authors.initials: P
authors.lastname: Sahbaie
authors.forename: De-Yong
authors.initials: DY
authors.lastname: Liang
authors.forename: Wen-Wu
authors.initials: WW
authors.lastname: Li
authors.forename: Xiang-Qi
authors.initials: XQ
authors.lastname: Li
authors.forename: Xiao-You
authors.initials: XY
authors.lastname: Shi
authors.forename: J David
authors.initials: JD
authors.lastname: Clark
mesh_terms: D048729:Anacardic Acids / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D015232:Dinoprostone / Q000008:administration & dosage / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D044127:Epigenesis, Genetic / Q000187:drug effects / Q000502:physiology*; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006877:Hydroxamic Acids / Q000494:pharmacology; D006930:Hyperalgesia / Q000209:etiology / Q000235:genetics*; D007150:Immunohistochemistry; D007432:Intraoperative Period; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D059225:Nociception / Q000502:physiology*; D010147:Pain Measurement / Q000187:drug effects; D010671:Phenylurea Compounds / Q000494:pharmacology; D010812:Physical Stimulation; D060888:Real-Time Polymerase Chain Reaction; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics* / Q000502:physiology*; D013116:Spinal Cord / Q000187:drug effects / Q000503:physiopathology*; D000077337:Vorinostat
chemical_list: D048729:Anacardic Acids; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D010671:Phenylurea Compounds; D023063:Receptors, Interleukin-8B; C112019:SB 225002; C088115:anacardic acid; D000077337:Vorinostat; D051548:Histone Acetyltransferases; D015232:Dinoprostone