title: Epigenetic regulation of opioid-induced hyperalgesia, dependence, and tolerance in mice.
abstract: Repeated administration of opioids such as morphine induces persistent behavioral changes including opioid-induced hyperalgesia (OIH), tolerance, and physical dependence. In the current work we explored how the balance of histone acetyltransferase (HAT) versus histone deacetylase (HDAC) might regulate these morphine-induced changes. Nociceptive thresholds, analgesia, and physical dependence were assessed during and for a period of several weeks after morphine exposure. To probe the roles of histone acetylation, the HAT inhibitor curcumin or a selective HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) was administered daily to groups of animals. Histone acetylation in spinal cord was assessed by Western blot and immunohistochemistry. Concurrent administration of curcumin with morphine for 4 days significantly reduced development of opioid-induced mechanical allodynia, thermal hyperalgesia, tolerance, and physical dependence. Conversely, the HDAC inhibitor SAHA enhanced these responses. Interestingly, SAHA treatment after the termination of opioid administration sustained these behavioral changes for at least 4 weeks. Histone H3 acetylation in the dorsal horn of the spinal cord was increased after chronic morphine treatment, but H4 acetylation was unchanged. Moreover, we observed a decrease in HDAC activity in the spinal cords of morphine-treated mice while overall HAT activity was unchanged, suggesting a shift toward a state of enhanced histone acetylation.
  
  
  CONCLUSIONS
  The current study indicates that epigenetic mechanisms play a crucial role in opioid-induced long-lasting neuroplasticity. These results provide new sight into understanding the mechanisms of opioid-induced neuroplasticity and suggest new strategies to limit opioid abuse potential and increase the value of these drugs as analgesics.
authors.affiliation: Department of Anesthesiology, Veterans Affairs Palo Alto Health Care System, Palo Alto, California 94304, USA. dyliang@stanford.edu
authors.forename: De-Yong
authors.initials: DY
authors.lastname: Liang
authors.forename: XiangQi
authors.initials: X
authors.lastname: Li
authors.forename: J David
authors.initials: JD
authors.lastname: Clark
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D015153:Blotting, Western; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis; D047369:Chromatin Immunoprecipitation; D003474:Curcumin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance / Q000235:genetics*; D044127:Epigenesis, Genetic; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006358:Hot Temperature; D006877:Hydroxamic Acids / Q000494:pharmacology; D006930:Hyperalgesia / Q000139:chemically induced* / Q000235:genetics* / Q000523:psychology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology; D009293:Opioid-Related Disorders / Q000235:genetics*; D010147:Pain Measurement / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects; D013375:Substance Withdrawal Syndrome / Q000523:psychology; D000077337:Vorinostat
chemical_list: D000701:Analgesics, Opioid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D019208:Brain-Derived Neurotrophic Factor; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat; D009020:Morphine; D003474:Curcumin