title: Morphine induces late cardioprotection in rat hearts in vivo: the involvement of opioid receptors and nuclear transcription factor kappaB.
abstract: Delta1-opioid receptor agonists can induce cardioprotection by early and late preconditioning (LPC). Morphine (MO) is commonly used for pain treatment during acute coronary syndromes. We investigated whether MO can induce myocardial protection by LPC and whether a nuclear transcription factor kappaB (NF-kappaB)-dependent intracellular signaling pathway is involved. Rats were subjected to 25 min of regional ischemia and 2 h of reperfusion 24 h after treatment with saline (NaCl; 0.9% 5 mL), lipopolysaccharide of Escherichia coli (LPS; 1 mg/kg), or MO (3 mg/kg). LPS is a trigger of LPC and served as positive control. Naloxone (NAL) was used to investigate the role of opioid receptors in LPC and was given before NaCl, LPS, or MO application (trigger phase) or before ischemia-reperfusion (mediator phase). Infarct size (percentage area at risk) was 59% +/- 9%, 51% +/- 6%, or 53% +/- 10% in the NaCl, NAL-NaCl, and NaCl-NAL groups, respectively. Pretreatment with MO reduced infarct size to 20% +/- 6% after 24 h (MO-24h), and this effect was abolished by NAL in the trigger (NAL-MO, 53% +/- 14%) and in the mediator (MO-NAL, 60% +/- 8%) phases. Pretreatment with LPS reduced infarct size to 23% +/- 8%. NAL administration in the trigger phase had no effect on infarct size (NAL-LPS 30% +/- 16%), whereas NAL during the mediator phase of LPC abolished the LPS-induced cardioprotection (LPS-NAL 54% +/- 8%). The role of NF-kappaB in morphine-induced LPC was investigated by Western blot and electrophoretic mobility shift assay. Morphine and LPS treatment increased phosphorylation of the inhibitory protein kappaB, leading to an increased activity of NF-kappaB. Thus, MO induces LPC similarly to LPS and it is likely that this cardioprotection is mediated at least in part by activation of NF-kappaB. Opioid receptors are involved as mediators in both MO- and LPS-induced LPC but as triggers only in MO-induced LPC.
  
  
  CONCLUSIONS
  Like lipopolysaccharide, morphine induces late preconditioning and activation of nuclear transcription factor-kappaB. Opioid receptors are involved as mediators in both morphine- and lipopolysaccharide-induced late preconditioning but as triggers only in morphine-induced late preconditioning.
authors.affiliation: Department of Anesthesiology, University Hospital of Düsseldorf, Düsseldorf, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Frässdorf
authors.forename: Nina C
authors.initials: NC
authors.lastname: Weber
authors.forename: Detlef
authors.initials: D
authors.lastname: Obal
authors.forename: Octavian
authors.initials: O
authors.lastname: Toma
authors.forename: Jost
authors.initials: J
authors.lastname: Müllenheim
authors.forename: Georg
authors.initials: G
authors.lastname: Kojda
authors.forename: Benedikt
authors.initials: B
authors.lastname: Preckel
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Schlack
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D024202:Electrophoretic Mobility Shift Assay; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D019157:Ischemic Preconditioning, Myocardial; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D009203:Myocardial Infarction / Q000517:prevention & control; D016328:NF-kappa B / Q000502:physiology*; D010766:Phosphorylation; D020011:Protective Agents / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011957:Receptors, Opioid / Q000502:physiology*
chemical_list: D008070:Lipopolysaccharides; D016328:NF-kappa B; D020011:Protective Agents; D011957:Receptors, Opioid; D009020:Morphine