We examined the possibility that the spleen or factor(s) derived from spleen mononuclear cells are involved in the deficient mu-opioid receptor-mediated analgesia encountered in diabetic mice. Splenectomized diabetic mice had a significantly higher sensitivity to morphine analgesia than untreated or sham-operated diabetic mice. Naive recipient mice injected with mononuclear spleen cells from diabetic mice exhibited a lower sensitivity to morphine analgesia than vehicle-treated naive mice. These results suggest that some factor(s) derived from spleen mononuclear cells may play an important, direct or indirect role in the selective reduction in mu-agonist-mediated analgesia in diabetic mice.