Abstract

The antinociceptive action of U-50,488H [( trans-(+/-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)- cyclohexyl]benzeneacetamide]), a selective kappa-opioid receptor agonist, was antagonized by serotonergic (5-HT) but not by noradrenergic receptor antagonists. U-50,488H (i.c.v.) was antagonized by more than 2-fold by i.c.v. administered pindolol, methysergide, mianserin, ketanserin or pirenperone. A similar degree of antagonism of U-50,488H (i.c.v.) was found after intrathecal (i.t.) treatments with pindolol or methysergide but not with mianserin, ketanserin or pirenperone. When U-50,488H was given i.t., its antinociceptive action was antagonized by pindolol or methysergide administered i.t. but potentiated by mianserin, ketanserin or pirenperone administered i.t. Tolerance to the antinociceptive action of U-50,488H was induced in mice using slow release preparations of U-50,488H. A smaller degree of cross-tolerance to the antinociceptive action of 5-HT also developed. 5-HT receptor antagonists (pindolol or ketanserin) were coadministered with U-50,488H to test for their effect on the development of tolerance to U-50,488H. A greater degree of tolerance was observed after ketanserin administration whereas the development of tolerance was partially blocked by the coadministration of pindolol. Changes in the properties of the kappa-opioid, 5-HT1 and 5-HT2 receptor binding sites in the cortical, striatal and spinal tissues of control and U-50,488H-tolerant mice were investigated. There were no significant changes in the maximum binding values of [3H]ethylketazocine, [3H]-5-HT or [3H]ketanserin. The Kd values of all ligands increased approximately 2-fold in most of the regions.(ABSTRACT TRUNCATED AT 250 WORDS)