JPET #64667 Page 1 Acute aspirin treatment abolishes while acute ibuprofen treatment enhances morphine- induced cardioprotection: role of 12-lipoxygenase

Patients suffering an acute myocardial infarction routinely receive morphine and NSAIDs alone or in combination. However, the importance of the dose, timing or the combined administration of both on infarct size reduction has not been assessed. Additionally, it is not known if morphine or NSAIDs require 12-lipoxygenase (12-LO) to mediate infarct size reduction as previously found for ischemic preconditioning. Male Sprague-Dawley rats were subjected to 30 minutes of ischemia and 2 hours of reperfusion, followed by infarct size assessment(Mean±SEM%, significance=**P<0.01). Morphine(0.3mg/kg), ibuprofen(3mg/kg) but not aspirin(3mg/kg), reduced infarct size when administered 5 minutes prior to reperfusion compared to vehicle(42.3±1.5**, 40.8±2.8**, 60.7±2.3 versus 59.1± 1.7%, respectively), however, none of these agents reduced infarct size when administered 10 seconds after reperfusion. Ibuprofen(3mg/kg) administered with morphine(0.3mg/kg) reduced infarct size(43.7±1.3%**) while aspirin(1 and 3mg/kg) abolished morphine-induced infarct size reduction. Morphine(0.2mg/kg) and ibuprofen(0.6mg/kg) given at doses not effective individually reduced infarct size when given together(59.0±1.4, 57.6±2.8, 43.9±1.6%**, respectively). Morphine and ibuprofen-induced infarct size reduction was abolished by the 12LO inhibitor, baicalein(3mg/kg) and mimicked by the 12-LO metabolite, 12(S)-HETE (45.2±2.5%**). These data suggest that morphine and ibuprofen reduce infarct size individually or at sub-threshold doses in combination via 12-LO when administered 5 minutes prior to reperfusion. Furthermore, acute aspirin administration has a detrimental interaction with morphine that abrogates morphine-induced infarct size reduction.