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 the electrophysiological effects of applied kappa opioids and endogenously released dynorphins. In hippocampal slices from drug-naive guinea pigs, application of U69,593, a kappa-1 agonist, produced a concentration-dependent inhibition (EC50 = 20 nM) of the amplitude of the granule cell population response in the dentate gyrus. In slices from chronically U50,488H-treated animals, the concentration-response curve for U69,593 was shifted 3-fold to the right (EC50 = 59 nM), with a significant decrease in the maximal effect of U69,593. We also found that the effects of endogenously released dynorphins were significantly attenuated by chronic U50,488H treatment. There was no cross-tolerance between kappa and mu opioid receptor agonists as measured with the in vitro electrophysiological assay, and the noncompetitive N-methyl-D-aspartate receptor antagonist MK801 did not prevent the development of tolerance to either the electrophysiological effects or the hypothermic effects of kappa opioids. Our study demonstrates that receptor-selective tolerance 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 inhibitory effects in the hippocampus did not depend on activation of N-methyl-D-aspartate receptors.