Post-resuscitation myocardial dysfunction is recognized as a leading cause of early death following initially successful cardiopulmonary resuscitation (CPR). In the present study, we hypothesized that a -opioid receptor agonist would decrease the severity of post-resuscitation myocardial dysfunction and improve survival. Fifteen Sprague-Dawley rats, fasted overnight with access to water, were anesthetized by an intraperitoneal injection of 45 mg/kg pentobarbital sodium. Additional doses of 10 mg/kg were administered at hourly intervals but not within 30 minutes preceding induced ventricular fibrillation (VF). Either the -opioid receptor agonist, pentazocine (300 µg/kg), pentazocine pre-treated with opioid receptor blocking agent, naloxone (1 mg/kg) or saline placebo was injected into the right atrium after 5 minutes of untreated VF and 3 minutes prior to starting CPR. After an additional 8 minutes of CPR, defibrillation was attempted. All animals were successfully resuscitated. Left ventricular dP/dt₄₀ and cardiac index (CI) were significantly improved in pentazocine-treated animals with significantly longer survival (60±11 vs 16±7 hours, P<0.01). Except for easy of defibrillation, the benefit effects of pentazocine were completely abolished by pre-treatment of naloxone. The concept of pharmacological hibernation employing a -opioid receptor agonist is a novel and promising intervention for minimizing global ischemic injury during CPR and post-resuscitation myocardial dysfunction.