The effects of chronic treatment with naltrindole (NTI), a selective delta-opioid receptor antagonist, on the antinociceptive effects of mu-opioid agonists, such as morphine and [D-Ala2, N-MePhe4, Gly-ol(5)]enkephalin (DAMGO) were examined in diabetic mice. Antinociception induced by morphine (10 micrograms, ICV) and DAMGO (0.5 microgram, ICV) was significantly lower in diabetic mice than in non-diabetic mice. The low sensitivities to the antinociceptive potencies of ICV morphine (10 micrograms) and DAMGO (0.5 micrograms) in diabetic mice were reversed compared with those in saline-treated non-diabetic mice when diabetic mice had been pretreated with NTI (2 mg/kg per day, SC) for 14 days. Naive mice which had been injected with spleen mononuclear cells from saline-treated diabetic mice were less sensitive to DAMGO-induced antinociception. However, adoptive transfer of spleen mononuclear cells from NTI-treated diabetic mice to naive mice had no effect on the recipients' antinociceptive sensitivity to DAMGO. These results suggest that the effect of NTI on the sensitivity to mu-opioid agonists in diabetic mice may be due to the immunosuppressive effects of NTI.