Corticotropin-releasing factor (CRF), a 41-residue peptide, inhibits the edema and protein extravasation produced by heat applied to the rat pawskin. Here, the time course of CRFs actions against heat-induced swelling was investigated. The paws of pentobarbital-anesthetized rats were immersed in 58 degrees C water for 30 sec and the resultant swelling was measured by the fluid displacement method. Human/rat CRF, 28 micrograms/kg s.c., injected 0.5 to 2 hr before heat exposure reduced swelling by over 50%. Pretreatment at 4 hr before heat was also effective, but not at 12 or 24 hr. CRF, injected 28 micrograms/kg i.v. 0, 10 or 20 min after heat exposure, inhibited the progressive development of swelling immediately. Histological examination of skin showed that CRF, given before or after heat, reduced vesication, edema, epidermal necrosis and the disruption of tissue architecture produced by thermal injury. The alpha-helical CRF(9-41) antagonist administered alone, 92 micrograms/kg i.v., before or after heat did not affect heat injury. The antagonist, however, both prevented and reversed the inhibitory effects of CRF on the swelling produced by heat. The antagonist-induced reversal occurred as late as 2 hr after CRF, 28 micrograms/kg s.c. Overall, these results suggested that CRF is a potent and efficacious agent in protecting skin against experimental thermal injury.