Abstract
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 betweenkappa 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 ofkappa 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 tokappa opioid analgesia, the inhibitory effects in the hippocampus did not depend on activation of N-methyl-d-aspartate receptors.
Footnotes
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Send reprint requests to: Dr. Charles Chavkin, Department of Pharmacology, Box 357280, University of Washington, Seattle, WA 98195-7280.
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↵1 Supported by a USPHS grant from NIDA, DA04123 (to C. C.) and an NIDA postdoctoral award, DA05734 (to W. J.).
- Abbreviations:
- nBNI
- norbinaltorphimine
- DAMGO
- [d-Ala2,NMePhe4, glyol5]enkephalin
- NMDA
- N-methyl-d-aspartate
- LTP
- long term potentiation
- s.c.
- subcutaneous
- S1/2
- stimulus intensity that evoked a half-maximal response
- Received August 12, 1996.
- Accepted December 13, 1996.
- The American Society for Pharmacology and Experimental Therapeutics