title: Kappa-opioid receptor-mediated antinociception in the rat. II. Supraspinal in addition to spinal sites of action.
abstract: This study examines whether there is a supraspinal, in addition to spinal, component to the antinociceptive actions against heat and pressure stimuli of kappa-opioid receptor agonists (U-69,593, U50,488H, bremazocine and tifluadom) as compared to mu-opioid receptor agonists (Tyr-D-Ala-Gly-NMe-Gly-ol, fentanyl and morphine) in the rat. The antinociception induced by kappa- and mu-opioids (applied s.c.) was unaffected by systemic quaternary naltrexone (50 mg/kg) revealing that it is mediated in the central nervous system. All kappa- and mu-opioids produced dose-dependent antinociception upon intrathecal application, in each case reversible by naloxone (5 mg/kg s.c.). However, intrathecal application of naloxone could only partially (by ca. 50%) antagonize the antinociception evoked by systemically applied U50,488H and morphine: this suggests sites of action in brain in addition to spinal cord for both mu- and kappa-opioids. Intraventricular application of mu-agonists produced maximal, dose-dependent antinociception. All kappa-agonists were also active in producing dose-dependent antinociception although curves were shallow and maximal antinociception could not be attained. The action of tifluadom was shown to be stereospecific. Naltrexone was 10-fold more potent in blocking morphine as compared to U50,488H whereas nor-binaltorphimine, a preferential kappa-antagonist, was 6-fold more potent against U50,488H than morphine. Indeed, whereas a dose of 0.2 mg/kg of naltrexone reversed mu-agonist actions, this dose was inactive against all kappa-agonists: the actions of these could be antagonized only by 2.0 mg/kg. These data indicate that in addition to kappa-receptors in the spinal cord, kappa-receptors in the brain can mediate antinociception against noxious heat and pressure.
authors.affiliation: Department of Neuropharmacology, Max-Planck-Institut for Psychiatry, Planegg-Martinsried, Federal Republic of Germany.
authors.forename: M J
authors.initials: MJ
authors.lastname: Millan
authors.forename: A
authors.initials: A
authors.lastname: Członkowski
authors.forename: A
authors.initials: A
authors.lastname: Lipkowski
authors.forename: A
authors.initials: A
authors.lastname: Herz
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects*; D008297:Male; D009020:Morphine / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D013116:Spinal Cord / Q000187:drug effects*
chemical_list: D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D011759:Pyrrolidines; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D009020:Morphine