Epigenetic regulation of spinal cord gene expression contributes to enhanced postoperative pain and analgesic tolerance subsequent to continuous opioid exposure.
BACKGROUND
Opioids have become the mainstay for treatment of moderate to severe pain and are commonly used to treat surgical pain. While opioid administration has been shown to cause opioid-induced hyperalgesia and tolerance, interactions between opioid administration and surgery with respect to these problematic adaptations have scarcely been addressed. Accumulating evidence suggests opioids and nociceptive signaling may converge on epigenetic mechanisms in spinal cord to enhance or prolong neuroplastic changes. Epigenetic regulation of Bdnf (brain-derived neurotrophic factor) and Pdyn (prodynorphin) genes may be involved.


RESULTS
Four days of ascending doses of morphine treatment caused opioid-induced hyperalgesia and reduced opioid analgesic efficacy in mice. Both opioid-induced hyperalgesia and the reduced opioid analgesic efficacy were enhanced in mice that received hindpaw incisions. The expression of Bdnf and Pdyn (qPCR) was increased after morphine treatment and incision. Chromatin immunoprecipitation assays demonstrated that the Pdyn and Bdnf promoters were more strongly associated with acetylated H3K9 after morphine plus incision than in the morphine or incision alone groups. Selective tropomyosin-related kinase B (ANA-12) and κ-opioid receptor (nor-binaltorphimine) antagonists were administered intrathecally, both reduced hyperalgesia one or three days after surgery. Administration of ANA-12 or nor-binaltorphimine attenuated the decreased morphine analgesic efficacy on day 1, but only nor-binaltorphimine was effective on day 3 after incision in opioid-exposed group. Coadministration of histone acetyltransferase inhibitor anacardic acid daily with morphine blocked the development of opioid-induced hyperalgesia and attenuated incision-enhanced hyperalgesia in morphine-treated mice. Anacardic acid had similar effects on analgesic tolerance, showing the involvement of histone acetylation in the interactions detected.


CONCLUSIONS
Spinal epigenetic changes involving Bdnf and Pdyn may contribute to the enhanced postoperative nociceptive sensitization and analgesic tolerance observed after continuous opioid exposure. Treatments blocking the epigenetically mediated up-regulation of these genes or administration of TrkB or κ-opioid receptor antagonists may improve the clinical utility of opioids, particularly after surgery.
Department of Anesthesia, Stanford University School of Medicine, Stanford, CA, USA Anaesthesiology Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA psahbaie@stanford.edu.
Peyman
P
Sahbaie
Department of Anesthesia, Stanford University School of Medicine, Stanford, CA, USA Anaesthesiology Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA.
De-Yong
DY
Liang
Department of Anesthesia, Stanford University School of Medicine, Stanford, CA, USA Anaesthesiology Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA.
Xiao-You
XY
Shi
Department of Anesthesia, Stanford University School of Medicine, Stanford, CA, USA Anaesthesiology Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA.
Yuan
Y
Sun
Department of Anesthesia, Stanford University School of Medicine, Stanford, CA, USA Anaesthesiology Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA.
J David
JD
Clark
D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use*; D000701:Analgesics, Opioid / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D004361:Drug Tolerance; D004399:Dynorphins / Q000378:metabolism; D044127:Epigenesis, Genetic / Q000187:drug effects*; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006930:Hyperalgesia / Q000150:complications / Q000235:genetics / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology; D010149:Postoperative Pain / Q000188:drug therapy* / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism* / Q000601:surgery
D000700:Analgesics; D000701:Analgesics, Opioid; D019208:Brain-Derived Neurotrophic Factor; D004399:Dynorphins; D009020:Morphine; D051548:Histone Acetyltransferases
BDNF and dynorphin; Epigenetics; histone acetylation; incision; opioid-induced hyperalgesia