The effects of adrenal and gonadal steroids on the antinociceptive potency of parenteral morphine were studied in male rats. At all doses studied, dexamethasone pretreatment 30 min before morphine sensitized the animals to the effect of parenteral morphine. However, at higher doses of dexamethasone this sensitization was masked when dexamethasone was given 4 h before morphine by a cycloheximide-sensitive attenuating effect. This feature is not a specific glucocorticoid effect since testosterone showed similar characteristics. Estradiol-17β and progesterone, however, produced only a cycloheximide-sensitive attenuating response at 4 h. Deoxycorticosterone on the contrary had a cycloheximide-independent attenuating influence with both pretreatment schedules. Results of the present study indicate that morphine subsensitivity after castration or supersensitivity after adrenalectomy may be attributed to the relative lack of testosterone or mineralocorticoid in the respective conditions. Furthermore, in view of the fact that neither deoxycorticosterone nor adrenalectomy can affect the morphine sensitivity of castrated rats, the results also indicate that testosterone plays a rate-limiting role in determining the morphine sensitivity of the animals and that mineralocorticoids exert their effects indirectly via antagonism of testosterone action. © 1982.