KAPPA-OPIOID RECEPTOR TOLERANCE IN THE GUINEA-PIG HIPPOCAMPUS

We investigated whether chronic, in vivo administration of U50,488H, a kappa-1 opioid agonist, caused the development of tolerance to both t he electrophysiological effects of applied kappa opioids and endogenou sly released dynorphins. In hippocampal slices from drug-naive guinea pigs, application of U69,593, a kappa-1 agonist, produced a concentrat ion-dependent inhibition (EC50 = 20 nM) of the amplitude of the granul e cell population response in the dentate gyrus. In slices from chroni cally U50,488H-treated animals, the concentration-response curve for U 69,593 was shifted 3-fold to the right (EC50 = 59 nM), with a signific ant decrease in the maximal effect of U69,593. We also found that the effects of endogenously released dynorphins were significantly attenua ted by chronic U50,488H treatment. There was no cross-tolerance betwee n kappa and mu opioid receptor agonists as measured with the in vitro electrophysiological assay, and the noncompetitive N-methyl-D-aspartat e receptor antagonist MK801 did not prevent the development of toleran ce to either the electrophysiological effects or the hypothermic effec ts of kappa opioids. Our study demonstrates that receptor-selective to lerance to the kappa opioid actions in the guinea pig hippocampus does develop after chronic U50,488H treatment; but, unlike the mechanisms reported to underlie tolerance to kappa opioid analgesia, the inhibito ry effects in the hippocampus did not depend on activation of N-methyl -D-aspartate receptors.