Cerebral protective effect of eptazocine, a mu-antagonist-kappa-agonist, was investigated using mice subjected to hypoxia-anoxia. Eptazocine (1 to 10 mg/kg) prolonged the survival time of mice subjected to KCN (3 mg/kg, i.v.) injection in a dose-dependent manner, and this effect was completely inhibited by naloxone (5 mg/kg). EKC, U50,488H, opioid kappa-agonists, also had such an effect, but were weaker than eptazocine. In mice exposed to hypobaric hypoxia (190 mmHg), eptazocine (3, 10 mg/kg) and EKC (10 mg/kg) prolonged the survival time, but morphine (5 mg/kg) and pentazocine (10 mg/kg) shortened the time. The eptazocine effect was attenuated by either naloxone (5 mg/kg) or atropine (0.5 mg/kg), different from what was seen in the case of physostigmine and diazepam, and the combination of eptazocine (1 mg/kg) and physostigmine (0.075 mg/kg) had a potentiating effect. MR-2266, a selective kappa-receptor antagonist, inhibited the eptazocine effect more potently than naloxone. These results suggest that eptazocine elicited its cerebral protective effect via its binding with opioid kappa-receptors and probably an activation of the central cholinergic system.