Levels of endogenous opioids and effects of an opiate antagonist during regional cerebral ischemia in rats.

Changes in endogenous opioid concentrations and the effect of treatment with the opiate receptor antagonist WIN 44,441-3 (WIN) were evaluated after middle cerebral artery occlusion (MCA-O) in rats. Animals treated with WIN at doses of 0.4 to 400 micrograms/kg 15 min, 3 hr and 6 hr after MCA-O had significantly higher mean arterial blood pressure than saline controls (P less than .05). Twenty-four hours after MCA-O, WIN-treated rats had significantly greater recovery of EEG activity and higher neurological scores than the controls; these actions were greatest at a dose of 40 micrograms/kg (P less than .01). The neurological outcome correlated with recovery of the ipsilateral EEG (P less than .01). The mortality rate 24 hr after occlusion and the infarct size were not significantly different from controls. At 1 hr after MCA-O, there were no significant differences in regional concentrations of endogenous opioid peptides (dynorphin, Leu-enkephalin and beta-endorphin) between the injured and uninjured hemispheres. These are the first studies to evaluate the effects of an opiate antagonist over a wide dose range in cerebral ischemia. Dose-related beneficial actions were found with regard to several, but not all, outcome measures. The absence of regional opioid changes after regional ischemia, in contrast to previous studies of spinal cord ischemia and brain trauma, was unexpected, but may reflect limited regional and temporal sampling.