The effects of the highly selective delta opioid receptor antagonists naltrindole (NTI) for delta 1 and delta 2 naltriben (NTB) and naltrindole 5'-isothiocyanate (5'-NTII) for delta 2 and 7-benzylidenenaltrexone (BNTX) for delta 1 on the development of physical dependence on morphine were investigated in mice. Neither NTI (3 mg/kg, sc), NTB (0.5 mg/kg, sc), 5'-NTII (0.5 mg/kg, sc) nor BNTX (0.5 mg/kg, sc) suppressed the antinociception induced by morphine (10 mg/kg, sc). Pretreatment with NTI (3 mg/kg, sc), NTB (0.5, 1.0 mg/kg, sc) or 5'-NTII (0.5, 1.0 mg/kg, sc) during chronic treatment with morphine for 5 days significantly suppressed naloxone-induced body-weight loss in morphine-dependent mice. The incidence of jumping and body shakes in morphine-dependent mice that were pretreated with NTI. NTB or 5'-NTII were significantly lower than with morphine alone. Pretreatment with BNTX (0.5, 1.0 mg/kg, sc) during chronic treatment with morphine also significantly suppressed naloxone-induced body-weight loss in morphine-dependent mice, but this suppression was weaker than that by the antagonists. In contrast to mice that had been pretreated with NTI, NTB or 5'-NTII, the incidence of several withdrawal signs, such a jumping and body shakes, was not significantly affected in morphine-dependent mice that were pretreated with BNTX. These findings suggest that both delta 2 and delta 1 opioid receptors may play important roles in modulating the development of physical dependence on morphine.