The pharmacological effects of morphine or the postulated physiological opiate, .beta.-endorphin, were compared in adrenalectomized and sham control animals. Pretreatment of adrenalectomized rats and mice with dexamethasone 2 h before opiate injections abolished the adrenalectomy-induced sensitization to parenteral opiates. This effect of dexamethasone was completely blocked by cycloheximide, a protein-synthesis inhibitor. After parenteral injection of [3H]-morphine, total 3H counts in the blood and brains of adrenalectomized mice were greater than in sham controls; this effect was blocked by dexamethasone pretreatment. Administration of SKF 525-A [2-diethylaminoethyl-2,2-diphenylvalerate hydrochloride] before morphine produced results which suggest that this putative inhibitor of the mixed-function oxidase metabolizing enzyme system also alters opiate potency. Apparently, adrenalectomy decreased morphine metabolism which enhanced the parenteral potency of this opiate through increased bioavailability. The dexamethasone reversal of this effect appears to depend upon its de novo induction of protein components of the opiate-metabolizing system. The possibility that a physiological interplay between endorphins and corticosteroids exist was suggested by the dexamethasone blockade of both the pharmacological effects and the toxicity of i.v. .beta.-endorphin in adrenalectomized mice.