alpha-Melanocyte stimulating hormone (alpha-MSH) has important host defense properties, in part similar to those of corticosteroids. Previous research suggests that secretion of alpha-MSH and of ACTH are controlled separately. The relationship between release of alpha-MSH and the activity of the hypothalamic-pituitary-adrenal axis in the rabbit was examined by monitoring changes in circulating alpha-MSH, ACTH, and corticosterone in response to endotoxin and corticotropin-releasing hormone (CRH), both with and without dexamethasone pretreatment. Endotoxin (1 microgram/kg IV) did not cause alpha-MSH release, but it did increase plasma concentrations of ACTH and corticosterone. Similarly, CRH (1 and 10 micrograms/kg IV) did not affect plasma alpha-MSH, whereas it stimulated ACTH and corticosterone release. Dexamethasone pretreatment abolished the responses of ACTH and corticosterone to either stimulus and did not modify circulating alpha-MSH after CRH. In contrast, dexamethasone pretreatment did result in a significant increase in plasma alpha-MSH after a dose of endotoxin that was ineffective alone. These data indicate that corticosteroids can facilitate the release of alpha-MSH, a powerful anti-inflammatory hormone. Since corticosteroids are released with certain challenges, this facilitatory activity may be important to the host response.