EFFECT OF THE KAPPA-1 OPIOID AGONIST CI-977 ON ISCHEMIC BRAIN-DAMAGE AND CEREBRAL BLOOD-FLOW AFTER MIDDLE CEREBRAL-ARTERY OCCLUSION IN THE RAT

The effects of the kappa-1 opioid agonist CI-977 upon the volume of ischemic brain damage (defined using quantitative neuropathology) and local cerebral blood flow (CBF) (defined using quantitative [C-14]iodoantipyrine autoradiography) have been examined at 4 h and 30 min, respectively, after permanent middle cerebral artery (MCA) occlusion in halothane-anesthetised rats. Treatment with CI-977 (0.3 mg/kg, s.c.) 30 min before and 30 min after occlusion of the MCA reduced the volume of infarction in the cerebral hemisphere (reduced by 27% when compared to vehicle; P < 0.05) and cerebral cortex (reduced by 32%; P < 0.05), despite a marked and sustained hypotension, with only minimal effect on damage in the caudate nucleus. In the hemisphere contralateral to the occluded MCA, treatment with CI-977 (0.3 mg/kg, s.c.) 30 min prior to the induction of ischemia failed to demonstrate any significant effect on either the level of local CBF in any of the 25 regions examined or on the volume of low CBF determined by frequency distribution analysis. In the hemisphere ipsilateral to MCA occlusion, CI-977 failed to produce statistically significant alterations in either the level of local CBF in 23 of the 25 regions or on the volume of low CBF, but areas of hyperemia were observed in both the medial caudate nucleus and lateral thalamus (local CBF increased by 65% and 86%, respectively, when compared to vehicle). The results of the present study indicate that the kappa-1 opioid agonist CI-977 is neuroprotective in a rat model of focal cerebral ischemia where key physiological variables have been assessed throughout the entire post-ischemic period, and fail to demonstrate that the neuroprotective effects of CI-977 in this model are due to improved blood flow to ischemic tissue.