title: Kappa opioid receptor tolerance in the guinea pig hippocampus.
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 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.
authors.affiliation: Department of Pharmacology, University of Washington, Seattle 98195-7280, USA.
authors.forename: W
authors.initials: W
authors.lastname: Jin
authors.forename: G W
authors.initials: GW
authors.lastname: Terman
authors.forename: C
authors.initials: C
authors.lastname: Chavkin
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000818:Animals; D044482:Benzeneacetamides; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004361:Drug Tolerance; D006168:Guinea Pigs; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D011759:Pyrrolidines / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D017473:Receptors, Opioid, kappa / Q000187:drug effects*; D017450:Receptors, Opioid, mu / Q000187:drug effects
chemical_list: D044482:Benzeneacetamides; D011759:Pyrrolidines; D016194:Receptors, N-Methyl-D-Aspartate; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D016291:Dizocilpine Maleate; C045444:U 69593