The immunomodulatory effects of opiates can modify host defenses against infection. We investigated the mechanisms involved in these effects by studying the influence of morphine on the pathogenesis of murine Friend retrovirus infection. The response to this opiate varied greatly according to the treatment schedule. Daily intra-peritoneal administration of morphine (50 mg/kg) for 16 to 27 days attenuated pathological manifestations in infected animals without modifying the mortality rate. The protective effect increased proportionately with the duration of treatment, and depended on the time of treatment initiation relative to inoculation. Naloxone (10 mg/kg/day i.p.) inhibited the morphine-induced decrease in both splenomegaly and viral titer. Mifepristone--a glucocorticoid receptor inhibitor--had no significant effect on the morphine-induced attenuation of splenomegaly. The influence of the infection on acute morphine toxicity was also analysed, using a non lethal dose in noninfected mice (200 mg/kg). Susceptibility to morphine increased in parallel to the development of the infection, with mortality rates ranging from 20% on D14 to 90% on D21. Simultaneous administration of naloxone (20-100 mg/kg) reduced the mortality rate and postponed death. Administration of mifepristone, terfenadin, phentolamine or propranolol did not modify mortality at the used doses. These findings show that the influence of morphine on the development of Friend virus infection in mice depends on the conditions of administration. The transient protective effect seen in certain conditions of administration seems to be due essentially to the direct effects of morphine on its specific receptors.