Systemically-administered morphine reduces infarct size in rat models of myocardial ischemia-reperfusion. We sought to determine whether much smaller doses of spinally-administered morphine offer a similar cardioprotective benefit. Barbiturate-anesthetized, open-chested, Wistar rats with chronic indwelling thoracic intrathecal catheters were instrumented for hemodynamic measurements and subjected to 30 min of coronary occlusion and 90 min of reperfusion. Myocardial infarct size was determined using triphenyl-tetrazolium staining. Rats were randomly assigned to receive intrathecal (IT) 0.9% saline (vehicle), IV morphine (0.3 mg/kg) plus IT saline, small-dose IT morphine (0.3 microg/kg), or large-dose IT morphine (3 microg/kg) 20 min before occlusion. IV and both doses of IT morphine reduced infarct size, defined as area of necrosis expressed as a percentage of area at risk (%AN/AAR), as compared with vehicle. The %AN/AAR group means were as follows: IV (n = 7), 30% +/- 6%; IT(small-dose) (n = 9), 30% +/- 5%; IT(large-dose) (n = 9), 18% +/- 4%; and vehicle (n = 10), 47% +/- 5%. There were no significant differences in infarct size among the morphine-pretreated rats. During ischemia-reperfusion, heart rate was unchanged from baseline in the IT(large-dose) group, whereas in the IT(small-dose), IV and vehicle groups, significant declines in heart rate occurred. Changes in arterial blood pressure were similar among groups. These results indicate that IT morphine reduces infarct size in rats, and this benefit is as great as that provided by IV morphine administration. CONCLUSIONS Our findings suggest that spinally-administered morphine provides a previously unrecognized cardioprotective benefit. In anesthetized rats subjected to ischemia-reperfusion injury, we show that very small doses of intrathecal morphine reduce infarct size in rats, and this benefit is as great as that provided by much larger doses of IV morphine.