Unilateral occlusion of the right common carotid artery in adult gerbils produced right homolateral cerebral ischemia and neurologic deficits (stroke) in 41.4% (Group S). The other 58.6% of the gerbils did not develop signs of stroke (Group N). Brains from gerbils of both groups were analyzed for levels of 8 immunoreactive neuropeptides and 4 CNS-receptor bindings. The level of β-endorphin was 90% higher in the ischemic right hemisphere than in the control left hemisphere, although the levels of the other 7 neuropeptides, i.e., Met-enkephalin (ENK), dynorphin, thyrotropin releasing hormons (TRH), cholecystokinin-oktapeptide, substance P, somatostatin and vasoactive intestinal polypeptide (VIP), were not different between the two hemispheres. However, the dynorphin level in the right hemisphere of Group S was significantly lower than that in the right hemisphere of Group N. Opioid receptor bindings were significantly lower in the ischemic hemispheres than in the control hemispheres. On the other hand, ischemia did not produce any change in TRH receptor binding and VIP receptor binding in the brain. An intraperitoneal (i.p.) injection of the opiate antagonist naloxone (1mg/kg) reversed signs of stroke within 3-5 min in 20 of 20 Group S gerbils; the effect lasted for up to 20-30 min, after which stroke returned. Remarkably, 16 of 22 Group N gerbils injected i.p. with pentazocine (15mg/kg) 5 hr after ligation developed stroke within 10min. The pentazocine-induced stroke could be reversed by an i.p. injection of naloxone (10mg/kg). Injection of an enkephalin analogue (FK33824; 15mg/kg, i.p.) 5 hr after ligation also produced stroke in 14 other Group N gerbils. Without medication, all of the stroke gerbils died with in 12 to 28 hours, but with a subcutaneous implantation of a 10-mg pellet of naloxone, 20% of the gerbils lived for 4 weeks. These findings suggest that β-endorphin and opioid receptors may be involved in the pathophysiology of stroke.