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 k-receptor agonist with pharmacological properties different from those produced by k 1-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°C and 55°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°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 k-opioid receptor different from the k1-opioid receptor in cynomolgus monkeys.Keywords: k-Opioid agonist, Antinociceptive effect, TRK-820, Cynomolgus monkey, k -Opioid receptor subtype Systematic efforts in searching for compounds which selectively stimulate k -opioid receptors resulted in the development of the compound TRK-820, (-)-17-cyclopropylmethyl-3,14b-dihydroxy-4,5a-epoxy-6b-[N-methyl-trans-3-(3-furyl)acrylamide]morphinan hydrochloride. It has been demonstrated previously that TRK-820 possesses a highly selective k -opioid receptor agonistic activity in bioassays with isolated guinea pig ileum and mouse vas deferens preparations (1). TRK-820 is also a selective and centrally acting k-opioid agonist with antinociceptive and sedative activity in rodents (2). This is supported by the finding that the antinociception induced by TRK-820 is selectively inhibited by the pretreatment with the k -opioid receptor antagonist nor-binaltorphimine, but not by the m -opioid receptor antagonist naloxone and @-opioid receptor antagonist naltrindole. Unlike the other k-opioid agonist pentazocine, which blocks m-opioid receptors, TRK-820 has little or no m-opioid receptor antagonistic properties. In behavioral studies, TRK-820 does not produce any significant place aversion or place preference using an unbiased place preference conditioning procedure in mice (3), although other k-opioid receptor agonist...
