title: Coadministration of glycogen-synthase kinase 3 inhibitor with morphine attenuates chronic morphine-induced analgesic tolerance and withdrawal syndrome.
abstract: BACKGROUND
  Glycogen-synthase kinase 3 (GSK3) is involved in many signaling pathways and is associated with a host of high-profile pathophysiological states. However, its role in morphine tolerance, especially naloxone-precipitated withdrawal syndrome, has not been well investigated. The present study was undertaken to study the role of GSK3 in chronic morphine exposure.
  
  
  METHODS
  Adult male Sprague-Dawley rats were subjected to intraperitoneal (i.p.) injections of morphine (10 mg/kg) twice daily for 6 consecutive days, and tail-flick tests were conducted to evaluate changes of morphine-induced antinociception. GSK3 inhibitor, SB216763 or SB415286, was i.p. injected prior to morphine to investigate the influences on morphine tolerance. There were four groups receiving morphine plus vehicle (2% dimethyl sulfoxide), morphine plus SB216763 (0.6 mg/kg) or SB415286 (1.0 mg/kg), GSK3 inhibitor alone, or dimethyl sulfoxide: as the control group. On Day 7, naloxone (i.p., 1 mg/kg) was administered and naloxone-precipitated withdrawal behaviors were individually compared between groups.
  
  
  RESULTS
  Repeated morphine exposure in this study led to progressive shortening of tail-flick latencies and produced six of nine observed naloxone-precipitated withdrawal behaviors. Coadministration with SB216763 or SB415286 significantly prevented antinociceptive tolerance and alleviated parts of withdrawal syndrome. Both inhibitors could similarly reverse withdrawal behaviors including grooming, chewing, and ptosis, but did not affect withdrawal behaviors of penis licking and defecation.
  
  
  CONCLUSIONS
  The results demonstrate the importance of GSK3 in reducing chronic morphine-induced tolerance and withdrawal syndrome. Although GSK3 is involved in diverse physiological functions, aiming at GSK3-related pathway could still be a potential tool to improve therapeutic quality in clinical morphine treatment.
authors.affiliation: Department of Anesthesiology, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan, ROC; School of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan, ROC.
authors.forename: Wen-Wei
authors.initials: WW
authors.lastname: Liao
authors.affiliation: Department of Anesthesiology, School of Medicine, China Medical University, Taichung, Taiwan, ROC.
authors.forename: Shih-Ying
authors.initials: SY
authors.lastname: Tsai
authors.affiliation: Central Laboratory, Shin-Kong Wu-Ho-Su Memorial Hospital, Taipei, Taiwan, ROC.
authors.forename: Chia-Chi
authors.initials: CC
authors.lastname: Liao
authors.affiliation: Department of Anesthesiology, School of Medicine, China Medical University, Taichung, Taiwan, ROC; Department of Anesthesiology, China Medical University Hospital, Taichung, Taiwan, ROC.
authors.forename: Kuen-Bao
authors.initials: KB
authors.lastname: Chen
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC; Department of Pediatric, Taipei Medical University Hospital, Taipei, Taiwan, ROC.
authors.forename: Geng-Chang
authors.initials: GC
authors.lastname: Yeh
authors.affiliation: Department of Anesthesiology, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan, ROC; School of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan, ROC.
authors.forename: Jui-Yuan
authors.initials: JY
authors.lastname: Chen
authors.affiliation: Department of Anesthesiology, School of Medicine, China Medical University, Taichung, Taiwan, ROC; Department of Anesthesiology, China Medical University Hospital, Taichung, Taiwan, ROC; Center for Pain Management and Research, China Medical University Hospital, Taichung, Taiwan, ROC; Graduate Institute of Acupuncture Science, College of Chinese Medicine, China Medical University, Taichung, Taiwan, ROC. Electronic address: yr.wen@yahoo.com.tw.
authors.forename: Yeong-Ray
authors.initials: YR
authors.lastname: Wen
mesh_terms: D000627:Aminophenols / Q000008:administration & dosage; D000818:Animals; D004338:Drug Combinations; D004361:Drug Tolerance / Q000502:physiology*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000502:physiology; D007211:Indoles / Q000008:administration & dosage; D008297:Male; D008301:Maleimides / Q000008:administration & dosage; D009020:Morphine / Q000008:administration & dosage*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013375:Substance Withdrawal Syndrome / Q000201:enzymology
chemical_list: C417520:3-(3-chloro-4-hydroxyphenylamino)-4-(4-nitrophenyl)-1H-pyrrole-2,5-dione; D000627:Aminophenols; D004338:Drug Combinations; D007211:Indoles; D008301:Maleimides; D047428:Protein Kinase Inhibitors; C417521:SB 216763; D009020:Morphine; D038362:Glycogen Synthase Kinase 3
keywords: glycogen synthase kinase; morphine tolerance; naloxone; withdrawal