1 Dermorphin and Hyp6-dermorphin are the first representatives of a new class of potent opioid peptides occurring in amphibian skin. They present the unique feature of having a D-Ala residue incorporated in the peptide molecule. 2 Dermorphin displayed a potent depressive action on electrically stimulated contractions of the guinea-pig ileum and mouse vas deferens preparations. Dermorphin was respectively 57,294, 18 and 39 times more potent than Met-enkephalin, Leu-enkephalin, beta-endorphin, and morphine on the guinea-pig ileum opiate receptors. On the vas deferens receptors, dermorphin was about as potent as the enkephalins and 40 times more potent than morphine. Naloxone was a powerful antagonist to dermorphin in both preparations. 3 Dermorphin produced potent and long-lasting analgesia in mice by intravenous injection, and in rats by intracerebroventricular injection, the ED50 being here of the order of 13-23 pmol/rat. Morphine was 752 and 2170 times less potent, depending on the analgesia test used. At high intracerebroventricular doses analgesia was accompanied by catalepsy. 4 Intracerebroventricular infusion of dermorphin induced development of tolerance and precipitation of withdrawal symptoms upon administration of naloxone. Both tolerance and physical dependence was consistently less marked with dermorphin than with morphine. 5 The minimum sequence requirement for full dermorphin activity was represented by the N-terminal tetrapeptide. The presence of the D-Ala2-residue was of crucial importance.