TRK-820, a selective kappa-opioid agonist, produces potent antinociceptionin cynomolgus monkeys

TRK-820 ((-)-17-cyclopropylmethyl-3,14b-dihydroxy-4,5a-epoxy-6b-[N-methyl-t rans-3-(3-furyl)acrylamide]morphinan hydrochloride) has been shown to be a potent opioid kappa -receptor agonist with pharmacological properties diffe rent from those produced by kappa (1)-opioid receptor agonists in rodents. To ascertain whether or not these properties of TRK-820 would be extended t o primates, the antinociceptive effect of TRK-820 was evaluated in cynomolg us monkeys by the hot-water tail-withdrawal procedure. TRK-820 given intram uscularly (i.m.) produced a potent antinociceptive effect that was 295- and 495-fold more potent than morphine with the 50 degreesC and 55 degreesC ho t-water tests, respectively, and 40-fold more potent than U-50,488H and 1,0 00-fold more potent than pentazocine in the 50 degreesC 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-50,4 88H. 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.) o r 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-binaltorphimi ne (10 mg/kg, s.c.). The same doses of nor-binaltorphimine and naloxone eff ectively 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 r esults indicate that the antinociception induced by TRK-820 is less sensiti ve to nor-binaltorphimine and suggest that it is mediated by the stimulatio n of a subtype of K-opioid receptor different from the kappa (1)-opioid rec eptor in cynomolgus monkeys.