BACKGROUND: We investigated the involvement of central and peripheral opioid receptors (OR) in the cardioprotective effects of fentanyl (FENT) in a model of myocardial ischemia/reperfusion injury associated with pharmacologically induced sympathetic overactivity in anesthetized rabbits. METHODS: Central sympathetic stimulation was achieved through intracerebroventricular injection of l-glutamate in animals submitted to 35 min of coronary occlusion followed by 120 min of reperfusion. Rabbits received naloxone HCl intracerebroventricularly or naloxone methiodide IV, a quaternary compound that does not cross the blood–brain barrier, 5 min before FENT treatment (5 or 50μg/kg, IV). RESULTS: Infarct area was reduced only by FENT 50 (from 51% ± 2% to 24% ± 2%). This protective effect was abolished by peripheral (42% ± 4%), but not central, OR blockade (32% ± 3%). The number of premature ventricular complexes during the ischemic period (54 ± 3) was reduced by FENT 50 (19 ± 7), an effect blunted by central (40 ± 3) but not peripheral (18 ± 7) blockade of OR. During reperfusion, the number of premature ventricular complexes (134 ± 50) was reduced to 9 ± 5 by FENT 50 and was prevented by central (42 ± 4) as well as peripheral (20 ± 11) OR blockade. The mortality rate (50%) and incidence of ventricular tachycardia (55%) were completely abolished by FENT 50. CONCLUSIONS: We conclude that fentanyl’s effects for limiting myocardial ischemic injury are mediated via peripheral ORs while opioid’s antiarrhythmic actions are mediated via central OR agonism.