Morphine has been shown to affect cell-mediated and humoral immune parameters. In this study, we investigated the capacity of in vivo acute and chronic morphine treatment to modulate interleukin (IL)-10 and IL-12 production by LPS and interferon-gamma-stimulated resident and thioglycollate-elicited murine peritoneal macrophages and the development of tolerance to these effects. One hour after the acute administration of 5, 10, and 20 mg/Kg morphine, a dose-related decrease of IL-10 and IL-12 levels was present. The pretreatment with naltrexone at doses up to 20 mg/Kg did not prevent the decrease of IL-10 and IL-12 induced by morphine. When the drug was administered chronically, a differential development of tolerance to the immune effects was observed. After 3 days of treatment, the effect of the acute challenge with 20 mg/Kg morphine on IL-12 was lost. In contrast, morphine-induced inhibition of IL-10 disappeared between 10 and 12 days of treatment, in parallel with tolerance to the antinociceptive effect. These results suggest that morphine treatment affects macrophage cytokine production and that tolerance affects this modulation differently.