title: Involvement of neuronal TGF-β activated kinase 1 in the development of tolerance to morphine-induced antinociception in rat spinal cord.
abstract: OBJECTIVE
  Tolerance induced by morphine and other opiates remains a major unresolved problem in the clinical management of pain. There is now good evidence for the importance of MAPKs in morphine-induced antinociceptive tolerance. A member of the MAPK kinase kinase family, TGF-β activated kinase 1 (TAK1) is the common upstream kinase of MAPKs. Here, we have assessed the involvement of TAK1 in the development of tolerance to morphine-induced analgesia.
  
  
  METHODS
  The effects of an antagonist of TAK1 on morphine tolerance were investigated in vivo using the Randall-Selitto test, and the mechanism was investigated using Western blot and immunohistochemistry. The expression of TAK1 after chronic morphine exposure was also evaluated in vitro by immunohistochemistry.
  
  
  RESULTS
  Chronic intrathecal morphine exposure up-regulated protein levels and phosphorylation of spinal TAK1. TAK1 immunoreactivity was co-localized with the neuronal marker NeuN. Intrathecal administration of 5Z-7-oxozeaenol (OZ), a selective TAK1 inhibitor, attenuated the loss of morphine analgesic potency and morphine-induced TAK1 up-regulation. Furthermore, OZ decreased the up-regulated expression of spinal p38 and JNK after repeated morphine exposure. In vitro studies demonstrated that sustained morphine treatment induced TAK1 up-regulation, which was reversed by co-administration of OZ. A bolus injection of OZ showed some reversal of established morphine antinociceptive tolerance.
  
  
  CONCLUSIONS
  TAK1 played a pivotal role in the development of morphine-induced antinociceptive tolerance. Modulation of TAK1 activation by the selective inhibitor OZ in the lumbar spinal cord may prove to be an attractive adjuvant therapy to attenuate such tolerance.
authors.affiliation: Department of Anesthesiology, Shanghai Jiaotong University Affiliated Shanghai Sixth People's Hospital, Shanghai, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Anesthesiology, Shanghai Jiaotong University Affiliated Shanghai Sixth People's Hospital, Shanghai, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Xu
authors.affiliation: Department of Anesthesiology, Shanghai Jiaotong University Affiliated Shanghai Sixth People's Hospital, Shanghai, China.
authors.forename: Xiaqing
authors.initials: X
authors.lastname: Ma
authors.affiliation: Department of Anesthesiology, Shanghai Jiaotong University Affiliated Shanghai Sixth People's Hospital, Shanghai, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Jiang
mesh_terms: D000698:Analgesia; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D004361:Drug Tolerance; D007150:Immunohistochemistry; D060186:Infusions, Spinal; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D059225:Nociception / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism; D015854:Up-Regulation; D015025:Zearalenone / Q000031:analogs & derivatives / Q000494:pharmacology / Q000008:administration & dosage; D000099151:MAP Kinase Kinase Kinase 7; D007783:Lactones; D012118:Resorcinols
chemical_list: D000701:Analgesics, Opioid; D020930:MAP Kinase Kinase Kinases; D009020:Morphine; D015025:Zearalenone; D000099151:MAP Kinase Kinase Kinase 7; C505734:7-oxozeanol; D007783:Lactones; D012118:Resorcinols