The effects of the novel kappa-opioid receptor agonist 17-cyclopropylmethyl-3,14beta-dihydroxy-4, 5alpha-epoxy-6beta-[N-methyl-trans-3-(3-furyl)acrylamido+ ++]morphinan hydrochloride (TRK-820) on the development of antinociceptive tolerance to morphine were investigated in mice and compared with those of trans-3,4-dichloro-N-(2-(1-pyrrolidinyl)-cyclohexyl) benzenacetamide methane sulfonate hydrochloride (U-50,488H), a well-defined exogenous kappa-opioid receptor agonist. Morphine (1. 25-20 mg/kg, s.c.) produced a dose-related antinociceptive effect in the 51 degrees C warm-plate test. Daily treatment with morphine (10 mg/kg, s.c.) resulted in the development of antinociceptive tolerance. The development of antinociceptive tolerance to morphine was dose-dependently suppressed by the co-administration of U-50, 488H (1-10 mg/kg, s.c.) with morphine, but not TRK-820 (0.003-0.03 mg/kg, s.c.). These results suggest that TRK-820-sensitive kappa-opioid receptor subtypes may not be involved in modulating the development of antinociceptive tolerance to morphine.
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