Loperamide given intracerebroventricularly and intraperitoneally to rats provoked, like morphine, a plasma corticosterone increase 60 min after injection. Loperamide intracerebroventricularly was 3.73 times less active than morphine, while intraperitoneally it was 10.13 times more potent. This increase, associated with a significant elevation in the plasma ACTH concentration, was antagonized by naloxone (10 mg/kg i.p.) injected 30 min before loperamide. In hypophysectomized rats loperamide intraperitoneally did not affect the plasma corticosterone levels. We conclude that loperamide can stimulate corticosterone secretin from the adrenal gland via the opiate receptors and that this effect is mediated by a direct or indirect induction of ACTH release.