Immunomodulating drugs as diverse as alpha-interferon and cyclosporine have been reported to attenuate physical signs of morphine withdrawal in rats. On the basis of these results, the immune system has been claimed to be involved in opiate addiction. To assess whether this is the case, the effects of alpha-interferon and cyclosporine were studied on objective signs of morphine withdrawal in morphine-dependent rats. Rats made dependent upon morphine by implantation of a 75-mg morphine pellet were challenged three days later by naloxone (1 mg/kg). Pretreatment with alpha-interferon (150 U/g) or cyclosporine (15 mg/kg) did not attenuate the reduction in body weight or the behavioral suppression induced by naloxone in morphine-dependent rats trained to press a lever for food reinforcement on a fixed-ratio 10 schedule. Alpha-interferon pretreatment blocked the capacity of naloxone to decrease body temperature in these rats and actually induced an hyperthermic response. In contrast, cyclosporine tended to enhance the drop in body temperature induced by naloxone. This last effect was more striking when the rats were placed in a cold room at 3.5 degrees C. Cyclosporine by itself induced a drop in body temperature in normal rats exposed to 3.5 degrees C. These results indicate that alpha-interferon and cyclosporine impair thermoregulation but do not directly interfere with morphine withdrawal signs.