We have recently demonstrated that the pineal neurohormone melatonin can enhance immune reactivity in normal mice and counteract the effects of acute stress or corticosterone treatment on antibody production, thymus weight and anti-viral resistance. These remarkable immunopharmacologic effects of melatonin were abolished by naltrexone, suggesting an involvement of the endogenous opioid system. Here we compared the immunopharmacologic action of beta-endorphin, dynorphin 1-13, leu-enkephalin and metenkephalin with that of melatonin in restraint-stressed or prednisolone-treated mice and in normal nonstressed animals. We found that beta-endorphin and dynorphin 1-13 can mimic the immunoenhancing and antistress effect of melatonin. However, at variance with the pineal neurohormone, these opioids were effective in umprimed mcie, too. We found also that restraint stress or prednisolone treatment decreases the immunopharmacologic potency of beta-endorphin and augments that of dynorphin 1-13. In fact, at the doses used, beta-endorphin enhanced the antibody response in normal but not in stressed or prednisolone-treated mice, while dynorphin 1-13 was effective only in counteracting the effect of stress or prednisolone treatment. Most interestingly, all these effects proved to be dependent on the time of administration, i.e. showed a circadian rhythm in analogy with the effects of melatonin. Again, naltrexone abolished all the opioid effects, indicating that their action was exerted via opioid receptors. These findings have important scientific and practical implications.