title: Potent antinociceptive effects of TRK-820, a novel kappa-opioid receptor agonist.
abstract: TRK-820, a new type of 4,5-epoxymorphinan derivative, was investigated in vivo for antinociceptive activities and its selectivity on various opioid receptors in mice. TRK-820 given s.c. or p.o. was found to be 351- and 796-fold more potent than U50,488H with acetic acid-induced abdominal constriction test. The duration of the antinociceptive effect produced by TRK-820 was longer than that produced by mu-opioid receptor agonist morphine or other kappa-opioid receptor agonists. In addition, with four other antinociceptive assays, low temperature hot plate (51 degrees C), thermal tail flick, mechanical tail pressure and tail pinch tests, TRK-820 was also found to be 68- to 328-fold more potent than U-50488H, and 41- to 349-fold more potent than morphine in producing antinociception, as comparing the weight of the different compound. However, TRK-820 was less active in inhibiting the high temperature (55 degrees C) hot plate response. The antinociceptive effects produced by TRK-820 were inhibited by nor-BNI, but not by naloxone or naltrindole (NTI) with the abdominal constriction test, indicating that the antinociception is selectively mediated by the stimulation of kappa-, but not mu- or delta-opioid receptors. Co-administration of TRK-820 with morphine slightly enhanced the antinociception induced by morphine in the mouse hot plate test. On the other hand, pentazocine significantly reduced the morphine-induced antinociception. TRK-820 produced sedation at doses, which are much higher than the doses for producing antinociception. These results indicate that the potent antinociception induced by TRK-820 is mediated via the stimulation of kappa-, but not mu- or delta-opiod receptors.
authors.affiliation: Basic Research Laboratories, Toray Industries, Inc., Kanagawa, Japan. Takashi_Endo@nts.toray.co.jp
authors.forename: T
authors.initials: T
authors.lastname: Endoh
authors.forename: H
authors.initials: H
authors.lastname: Matsuura
authors.forename: A
authors.initials: A
authors.lastname: Tajima
authors.forename: N
authors.initials: N
authors.lastname: Izumimoto
authors.forename: C
authors.initials: C
authors.lastname: Tajima
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: L
authors.initials: L
authors.lastname: Tseng
authors.forename: H
authors.initials: H
authors.lastname: Nagase
mesh_terms: D000284:Administration, Oral; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D003251:Constriction, Pathologic / Q000139:chemically induced; D004347:Drug Interactions; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D009019:Morphinans / Q000008:administration & dosage / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects; D009619:Nociceptors / Q000187:drug effects*; D010423:Pentazocine / Q000494:pharmacology; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000037:antagonists & inhibitors; D013141:Spiro Compounds / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D018712:Analgesics, Non-Narcotic; D000701:Analgesics, Opioid; D006993:Hypnotics and Sedatives; D009019:Morphinans; D017473:Receptors, Opioid, kappa; D013141:Spiro Compounds; C111212:TRK 820; D010423:Pentazocine