U-50,488, (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]- benzeneacetamide hydrochloride), is a selective kappa-opioid receptor agonist. In this study, we found that U-50,488 antagonized morphine-induced antinociception in morphine-naive guinea pigs at doses which did not have any antinociceptive effect by themselves (0.01-3 mg/kg). On the other hand, U-50,488 (3 mg/kg) partially restored morphine-induced antinociception in morphine-tolerant guinea pigs (8 mg/kg/day i.p. morphine HCl for 6 days). Furthermore, the development of tolerance to morphine antinociception was completely blocked by coadministration of U-50,488 at a very low dose (0.003 mg/kg i.p.) which neither exerted an antinociceptive effect by itself nor affected the antinociception induced by 8 mg/kg of morphine HCl. The withdrawal signs induced by 8 mg/kg (i.p.) naloxone HCl on the 7th day were also depressed by coadministration of 0.003 mg/kg U-50,488 with morphine HCl (8 mg/kg i.p.) every day for 7 days. These effects of U-50,488 could be applied to humans to prevent morphine tolerance and dependence.