title: Epigenetic regulation of spinal cord gene expression controls opioid-induced hyperalgesia.
abstract: BACKGROUND
  The long term use of opioids for the treatment of pain leads to a group of maladaptations which includes opioid-induced hyperalgesia (OIH). OIH typically resolves within few days after cessation of morphine treatment in mice but is prolonged for weeks if histone deacetylase (HDAC) activity is inhibited during opioid treatment. The present work seeks to identify gene targets supporting the epigenetic effects responsible for OIH prolongation.
  
  
  RESULTS
  Mice were treated with morphine according to an ascending dose protocol. Some mice also received the selective HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) additionally. Chronic morphine treatment with simultaneous HDAC inhibition enhanced OIH, and several spinal cord genes were up-regulated. The expression of Bdnf (Brain-derived neurotrophic factor) and Pdyn (Prodynorphin) were most closely related to the observed behavioral changes. ChIP (Chromatin immuoprecipation) assays demonstrated that promoter regions of Pdyn and Bdnf were strongly associated with aceH3K9 (Acetylated histone H3 Lysine9) after morphine and SAHA treatment. Furthermore, morphine treatment caused an increase in spinal BDNF and dynorphin levels, and these levels were further increased in SAHA treated mice. The selective TrkB (tropomyosin-receptor-kinase) antagonist ANA-12 reduced OIH when given one or seven days after cessation of morphine. Treatment with the selective kappa opioid receptor antagonist nor-BNI also reduced established OIH. The co-administration of either receptor antagonist agent daily with morphine resulted in attenuation of hyperalgesia present one day after cessation of treatment. Additionally, repeated morphine exposure induced a rise in BDNF expression that was associated with an increased number of BDNF+ cells in the spinal cord dorsal horn, showing strong co-localization with aceH3K9 in neuronal cells. Lastly, spinal application of low dose BDNF or Dynorphin A after resolution of OIH produced mechanical hypersensitivity, with no effect in controls.
  
  
  CONCLUSIONS
  The present study identified two genes whose expression is regulated by epigenetic mechanisms during morphine exposure. Treatments aimed at preventing the acetylation of histones or blocking BDNF and dynorphin signaling may reduce OIH and improve long-term pain using opioids.
authors.forename: De-Yong
authors.initials: DY
authors.lastname: Liang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Sun
authors.forename: Xiao-You
authors.initials: XY
authors.lastname: Shi
authors.affiliation: Department of Anesthesia, Stanford University School of Medicine, Stanford, CA 94305, USA. psahbaie@stanford.edu.
authors.forename: Peyman
authors.initials: P
authors.lastname: Sahbaie
authors.forename: J David
authors.initials: JD
authors.lastname: Clark
mesh_terms: D000701:Analgesics, Opioid / Q000633:toxicity*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D001381:Azepines / Q000008:administration & dosage; D001549:Benzamides / Q000008:administration & dosage; D019208:Brain-Derived Neurotrophic Factor / Q000008:administration & dosage / Q000235:genetics; D004195:Disease Models, Animal; D004399:Dynorphins / Q000008:administration & dosage / Q000235:genetics; D044127:Epigenesis, Genetic / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D006877:Hydroxamic Acids / Q000008:administration & dosage; D006930:Hyperalgesia / Q000139:chemically induced* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000633:toxicity*; D009271:Naltrexone / Q000008:administration & dosage / Q000031:analogs & derivatives; D009292:Narcotic Antagonists / Q000008:administration & dosage; D010147:Pain Measurement / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*; D000077337:Vorinostat
chemical_list: C559317:ANA 12 compound; D000701:Analgesics, Opioid; D000970:Antineoplastic Agents; D001381:Azepines; D001549:Benzamides; D019208:Brain-Derived Neurotrophic Factor; D006877:Hydroxamic Acids; D009292:Narcotic Antagonists; C051844:norbinaltorphimine; D000077337:Vorinostat; D009271:Naltrexone; D004399:Dynorphins; D009020:Morphine