The effects of a novel kappa-opioid receptor agonist, TRK-820, on the development of physical dependence on morphine were investigated in mice in comparison with those of U-50,488H. A marked body weight loss and several withdrawal signs were observed following naloxone challenge in morphine-dependent mice. Co-injection of TRK-820 (0.003-0.03 mg/kg, s.c.) but not U-50,488H (1-10 mg/kg, s.c.) during chronic morphine treatment dose-dependently suppressed the naloxone-precipitated body weight loss, jumping, wet dog shakes and diarrhea. These results suggest that TRK-820-sensitive kappa-opioid receptor subtypes may play a significant role in modulating the development of physical dependence on morphine.