title: TRK-820, a selective kappa-opioid agonist, produces potent antinociception in cynomolgus monkeys.
abstract: TRK-820 ((-)-17-cyclopropylmethyl-3,14b-dihydroxy-4,5a-epoxy-6b-[N-methyl-trans-3-(3-furyl)acrylamide]morphinan hydrochloride) has been shown to be a potent opioid kappa-receptor agonist with pharmacological properties different from those produced by kappa1-opioid receptor agonists in rodents. To ascertain whether or not these properties of TRK-820 would be extended to primates, the antinociceptive effect of TRK-820 was evaluated in cynomolgus monkeys by the hot-water tail-withdrawal procedure. TRK-820 given intramuscularly (i.m.) produced a potent antinociceptive effect that was 295- and 495-fold more potent than morphine with the 50 degrees C and 55 degrees C hot-water tests, respectively, and 40-fold more potent than U-50,488H and 1,000-fold more potent than pentazocine in the 50 degrees C hot-water test. The duration of antinociceptive effects of TRK-820 treatment (0.01 and 0.03 mg/kg, i.m.) lasted more than 6 h, which was much longer than those of U-50,488H. The antinociception produced by the higher dose (0.03 mg/kg, i.m.) of TRK-820 was not inhibited by nor-binaltorphimine (3.2 and 10 mg/kg, s.c.) or by naloxone (0.1 mg/kg, s.c.), although the antinociception induced by a lower dose of TRK-820 (0.01 mg/kg, i.m.) was inhibited by nor-binaltorphimine (10 mg/kg, s.c.). The same doses of nor-binaltorphimine and naloxone effectively inhibited the antinociception induced by the higher doses of U-50,488H (1.0 mg/kg, i.m.) and morphine (10 mg/kg, i.m.), respectively. These results indicate that the antinociception induced by TRK-820 is less sensitive to nor-binaltorphimine and suggest that it is mediated by the stimulation of a subtype of kappa-opioid receptor different from the kappa-opioid receptor in cynomolgus monkeys.
authors.affiliation: Pharmaceutical Laboratories, Toray Industries Inc., Kamakura, Kanagawa, Japan. takashi_endo@nts.toray.co.jp
authors.forename: T
authors.initials: T
authors.lastname: Endoh
authors.forename: A
authors.initials: A
authors.lastname: Tajima
authors.forename: N
authors.initials: N
authors.lastname: Izumimoto
authors.forename: T
authors.initials: T
authors.lastname: Suzuki
authors.forename: A
authors.initials: A
authors.lastname: Saitoh
authors.forename: T
authors.initials: T
authors.lastname: Suzuki
authors.forename: M
authors.initials: M
authors.lastname: Narita
authors.forename: J
authors.initials: J
authors.lastname: Kamei
authors.forename: L F
authors.initials: LF
authors.lastname: Tseng
authors.forename: H
authors.initials: H
authors.lastname: Mizoguchi
authors.forename: H
authors.initials: H
authors.lastname: Nagase
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology; D000700:Analgesics / Q000494:pharmacology*; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D008252:Macaca fascicularis; D009019:Morphinans / Q000494:pharmacology*; D009020:Morphine / Q000494:pharmacology; D009270:Naloxone / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D010147:Pain Measurement; D010423:Pentazocine / Q000494:pharmacology; D010424:Pentobarbital / Q000494:pharmacology; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D013141:Spiro Compounds / Q000494:pharmacology*
chemical_list: D000700:Analgesics; D018712:Analgesics, Non-Narcotic; D000701:Analgesics, Opioid; D009019:Morphinans; D017473:Receptors, Opioid, kappa; D013141:Spiro Compounds; C111212:TRK 820; D009270:Naloxone; C051844:norbinaltorphimine; D009271:Naltrexone; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D009020:Morphine; D010424:Pentobarbital; D010423:Pentazocine