title: Serotonergic involvement in the antinociceptive action of and the development of tolerance to the kappa-opioid receptor agonist, U-50, 488H.
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)
authors.affiliation: Department of Pharmacology, Medical School, University of Minnesota, Minneapolis.
authors.forename: B Y
authors.initials: BY
authors.lastname: Ho
authors.forename: A E
authors.initials: AE
authors.lastname: Takemori
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D003496:Cyclazocine / Q000031:analogs & derivatives / Q000378:metabolism; D004361:Drug Tolerance; D016314:Ethylketocyclazocine; D007650:Ketanserin / Q000378:metabolism; D008297:Male; D051379:Mice; D010869:Pindolol / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology*; D011957:Receptors, Opioid / Q000187:drug effects*; D017473:Receptors, Opioid, kappa; D011985:Receptors, Serotonin / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000494:pharmacology; D013565:Sympatholytics / Q000494:pharmacology
chemical_list: D000700:Analgesics; D011759:Pyrrolidines; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013565:Sympatholytics; D016314:Ethylketocyclazocine; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D007650:Ketanserin; D010869:Pindolol; D003496:Cyclazocine