title: Leukemia inhibitory factor (LIF) potentiates antinociception activity and inhibits tolerance induction of opioids.
abstract: BACKGROUND
  The efficacy of opioids typically decreases after long-term use owing to the development of tolerance. Glial activation and the upregulation of proinflammatory cytokines are related to the induction of tolerance. We investigated the effect of leukemia inhibitory factor (LIF) on morphine analgesia and tolerance.
  
  
  METHODS
  LIF concentrations in rat spinal cords were measured by polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA) after morphine administration. LIF distribution was examined using confocal microscopy. To evaluate the effects of LIF on morphine analgesia and tolerance, LIF was intrathecally administered 30 min before morphine injection. The analgesic effect of morphine was evaluated by measuring tail-flick latency. Human LIF concentrations from the cerebrospinal fluid (CSF) of opioid tolerant patients were also determined by specific ELISA.
  
  
  RESULTS
  Chronic morphine administration upregulated LIF concentrations in rat spinal cords. Intrathecal injection of LIF potentiated the analgesic action of morphine. Patch clamp recording of spinal cord slices showed that LIF enhanced DAMGO ([D-Ala2, N-MePhe4, Gly-ol]-enkephalin)-induced outward potassium current. The development of tolerance was markedly suppressed by exogenous LIF, whereas neutralizing the endogenously released LIF with anti-LIF antibodies accelerated the tolerance induction. Moreover, LIF concentrations in the CSF of opioid-tolerant patients were higher than those in the opioid-naive controls.
  
  
  CONCLUSIONS
  Intrathecal administration of LIF potentiated morphine antinociceptive activity and attenuated the development of morphine tolerance. Upregulation of endogenously released LIF by long-term use of opioids might counterbalance the tolerance induction effects of other proinflammatory cytokines. LIF might be a novel drug candidate for inhibiting opioid tolerance induction.
authors.affiliation: Pharmacological Institute, College of Medicine, National Taiwan University, No.1, Sec.1, Jen-Ai Road, Taipei 100, Taiwan.
authors.forename: H J
authors.initials: HJ
authors.lastname: Tu
authors.affiliation: Pharmacological Institute, College of Medicine, National Taiwan University, No.1, Sec.1, Jen-Ai Road, Taipei 100, Taiwan.
authors.forename: K H
authors.initials: KH
authors.lastname: Kang
authors.affiliation: Department of Neurology, National Taiwan University Hospital, No. 7, Chung-Shan S. Road, Taipei 100, Taiwan.
authors.forename: S Y
authors.initials: SY
authors.lastname: Ho
authors.affiliation: Pharmacological Institute, College of Medicine, National Taiwan University, No.1, Sec.1, Jen-Ai Road, Taipei 100, Taiwan.
authors.forename: H C
authors.initials: HC
authors.lastname: Liou
authors.affiliation: Department of Neurology, National Taiwan University Hospital, No. 7, Chung-Shan S. Road, Taipei 100, Taiwan.
authors.forename: H H
authors.initials: HH
authors.lastname: Liou
authors.affiliation: Pharmacological Institute, College of Medicine, National Taiwan University, No.1, Sec.1, Jen-Ai Road, Taipei 100, Taiwan wenmei@ntu.edu.tw.|Department of Anaesthesiology.
authors.forename: C P
authors.initials: CP
authors.lastname: Lin
authors.affiliation: Pharmacological Institute, College of Medicine, National Taiwan University, No.1, Sec.1, Jen-Ai Road, Taipei 100, Taiwan wenmei@ntu.edu.tw.
authors.forename: W M
authors.initials: WM
authors.lastname: Fu
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D016207:Cytokines / Q000032:analysis; D004361:Drug Tolerance; D006801:Humans; D053605:Leukemia Inhibitory Factor / Q000502:physiology*; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000701:Analgesics, Opioid; D016207:Cytokines; D053605:Leukemia Inhibitory Factor; D009020:Morphine
keywords: glia; leukemia inhibitory factor; opioid