title: Morphine preconditions Purkinje cells against cell death under in vitro simulated ischemia-reperfusion conditions.
abstract: BACKGROUND
  Morphine pretreatment via activation of delta1-opioid receptors induces cardioprotection. In this study, the authors determined whether morphine preconditioning induces ischemic tolerance in neurons.
  
  
  METHODS
  Cerebellar brain slices from adult Sprague-Dawley rats were incubated with morphine at 0.1-10 microM in the presence or absence of various antagonists for 30 min. They were then kept in morphine- and antagonist-free buffer for 30 min before they were subjected to simulated ischemia (oxygen-glucose deprivation) for 20 min. After being recovered in oxygenated artificial cerebrospinal fluid for 5 h, they were fixed for morphologic examination to determine the percentage of undamaged Purkinje cells.
  
  
  RESULTS
  The survival rate of Purkinje cells was significantly higher in slices preconditioned with morphine (> or = 0.3 microM) before the oxygen-glucose deprivation (57 +/- 4% at 0.3 microM morphine) than that of the oxygen-glucose deprivation alone (39 +/- 3%, P < 0.05). This morphine preconditioning-induced neuroprotection was abolished by naloxone, a non-type-selective opioid receptor antagonist, by naltrindole, a selective delta-opioid receptor antagonist, or by 7-benzylidenenaltrexone, a selective delta1-opioid receptor antagonist. However, the effects were not blocked by the mu-, kappa-, or delta2-opioid receptor antagonists, beta-funaltrexamine, nor-binaltorphimine, or naltriben, respectively. Morphine preconditioning-induced neuroprotection was partially blocked by the selective mitochondrial adenosine triphosphate-sensitive potassium channel antagonist, 5-hydroxydecanoate, or the mitochondrial electron transport inhibitor, myxothiazol. None of the inhibitors used in this study alone affected the simulated ischemia-induced neuronal death.
  
  
  CONCLUSIONS
  These data suggest that morphine preconditioning is neuroprotective. This neuroprotection may be delta1-opioid receptor dependent and may involve mitochondrial adenosine triphosphate-sensitive potassium channel activation and free radical production. Because morphine is a commonly used analgesic, morphine preconditioning may be explored further for potential clinical use to reduce ischemic brain injury.
authors.affiliation: Department of Anesthesiology, University of Virginia Health System, Charlottesville 22908-0710, USA.
authors.forename: Young Jin
authors.initials: YJ
authors.lastname: Lim
authors.forename: Shuqiu
authors.initials: S
authors.lastname: Zheng
authors.forename: Zhiyi
authors.initials: Z
authors.lastname: Zuo
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002531:Cerebellum / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004579:Electron Transport / Q000187:drug effects; D005947:Glucose / Q000502:physiology; D000860:Hypoxia / Q000473:pathology; D066298:In Vitro Techniques; D019194:Ischemic Preconditioning; D008297:Male; D008565:Membrane Proteins / Q000187:drug effects / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D009020:Morphine / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000494:pharmacology; D009294:Narcotics / Q000494:pharmacology*; D018696:Neuroprotective Agents; D015221:Potassium Channels; D011689:Purkinje Cells / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000187:drug effects; D015427:Reperfusion Injury / Q000473:pathology*
chemical_list: D008565:Membrane Proteins; D009292:Narcotic Antagonists; D009294:Narcotics; D018696:Neuroprotective Agents; D015221:Potassium Channels; D017465:Receptors, Opioid, delta; C117780:mitochondrial K(ATP) channel; D009020:Morphine; D005947:Glucose