Quantitative analysis of effects of k-opioid agonists on postischemic hippocampal ca₁neuronal necrosis in gerbils

The ability of the K-opioid receptor agonists U50488H and U62066E (spiradoline mesylate) compared with the non-K close structural analogue U54494A to affect postischemic necrosis of the selectively vulnerable hippocampal CA, neurons was examined in male Mongolian gerbils. The gerbils were treated with either saline vehicle or 10 mg/kg i.p. of one of the test drugs 30 minutes before and again 2 hours after a 10-minute period of bilateral carotid artery occlusion or sham occlusion under light methoxyflurane anesthesia. Seven days after ischemia and reperfusion the brains were perfusion-fixed, and hippocampal CA, cells were counted in a blind fashion. In ischemic gerbils that received only vehicle, there was a 78.9% loss of CA, neurons compared with sham-occluded gerbils. In contrast, in U50488H-treated gerbils, mean cell loss was reduced to 33.9% (p<0.01 vs. vehicle-treated group). U62066E was even more effective in reducing postischemic CA, degeneration to only 20.7% (p<0.0001 vs. vehicle-treated group). However, treatment with the non-κ analogue U54494A did not cause any apparent protection; the gerbils in this group showed an 80.7% loss of CA₁ neurons. Our results are consistent with the hypothesis that κ-receptor stimulation is associated with improved postischemic neuronal preservation.