The peptidase-resistance of deltorphins (DEL-A, H-Tyr-D-Met-Phe-His-Leu-Met-Asp-NH2) and (DEL-C, H-Tyr-D-Ala-Phe-Asp-Val-Val-Gly-NH2), highly selective and potent agonists of the delta opioid receptor, were investigated in vitro. DEL-C was fully resistant to degradation by rat plasma and strongly resistant to degradation by rat brain homogenates. DEL-A was cleaved with a half-life of 131.6 min upon incubation with plasma, and 57.4 min with rat brain homogenates. N-terminal truncated sequences of DEL-A and -C with free carboxyl groups, were also analyzed for receptor binding activity using [3H] DADLE for delta sites and [3H] DAGO for mu sites. The high enzymatic stability associated with deltorphins and their degradation products may make them prime candidates to characterize the role of delta-receptors in vivo.