title: Melatonin reverses morphine tolerance by inhibiting microglia activation and HSP27 expression.
abstract: OBJECTIVE
  Melatonin has been reported to attenuate opioid tolerance. In this study, we explored the possible mechanism of melatonin in diminishing morphine tolerance.
  
  
  METHODS
  Two intrathecal (i.t.) catheters were implanted in male Wistar rats for drug delivery. One was linked to a mini-osmotic pump for morphine or saline infusion. On the seventh day, 50μg of melatonin or vehicle was injected through the other catheter instantly after discontinuation of morphine or saline infusion; 3h later, 15μg of morphine or saline was injected. The antinociceptive response was then measured using the tail-flick test every 30min for 120min.
  
  
  RESULTS
  The results showed that chronic morphine infusion elicited antinociceptive tolerance and upregulated heat shock protein 27 (HSP27) expression in the dorsal horn of the rat spinal cord. Melatonin pretreatment partially restored morphine's antinociceptive effect in morphine-tolerant rats and reversed morphine-induced HSP27 upregulation. In addition, chronic morphine infusion induced microglial cell activation and was reversed by melatonin treatment.
  
  
  CONCLUSIONS
  The present study provides evidence that melatonin, acting via inhibiting morphine-induced neuroinflammation, can be useful as a therapeutic adjuvant for patients under long-term opioid treatment for pain relief.
authors.affiliation: Graduate Institute of Medical Science, National Defense Medical Center, Taipei City, Taiwan; Medical Service Office, Tri-Service General Hospital Songshang Branch, Taipei City, Taiwan.
authors.forename: Sheng-Hsiung
authors.initials: SH
authors.lastname: Lin
authors.affiliation: Department of Nursing, Hsin Sheng Junior College of Medical Care and Management, Taoyuan City, Taiwan.
authors.forename: Ya-Ni
authors.initials: YN
authors.lastname: Huang
authors.affiliation: Department of Anesthesiology, Cathay General Hospital, Taipei City, Taiwan; Cathay Medical Research Institute, Cathay General Hospital, Taipei City, Taiwan.
authors.forename: Jen-Hsin
authors.initials: JH
authors.lastname: Kao
authors.affiliation: School of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan.
authors.forename: Lu-Tai
authors.initials: LT
authors.lastname: Tien
authors.affiliation: Department of Nursing, Da-Yeh University, Changhua City, Taiwan.
authors.forename: Ru-Yin
authors.initials: RY
authors.lastname: Tsai
authors.affiliation: Graduate Institute of Medical Science, National Defense Medical Center, Taipei City, Taiwan; Department of Anesthesiology, Cathay General Hospital, Taipei City, Taiwan; School of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan. Electronic address: w82556@gmail.com.
authors.forename: Chih-Shung
authors.initials: CS
authors.lastname: Wong
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D004361:Drug Tolerance; D005786:Gene Expression Regulation / Q000187:drug effects; D055551:HSP27 Heat-Shock Proteins / Q000819:agonists* / Q000096:biosynthesis*; D007278:Injections, Spinal; D008262:Macrophage Activation / Q000187:drug effects; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D017628:Microglia / Q000187:drug effects*; D009020:Morphine / Q000494:pharmacology*; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000701:Analgesics, Opioid; D055551:HSP27 Heat-Shock Proteins; C486114:Hspb1 protein, rat; D009020:Morphine; D008550:Melatonin
keywords: Antinociception; Heat shock protein 27; Intrathecal injection; Melatonin; Microglial activation; Morphine tolerance; Neuroinflammation; Tail-flick latency