ABSTRACT: In amphibians, α-MSH secreted by the pars intermedia of the pituitary plays a pivotal role in the process of skin color adaptation. Reciprocally, the skin of amphibians contains a number of regulatory peptides, some of which have been found to regulate the activity of pituitary melanotrope cells. In particular, the skin of certain species of amphibians harbours considerable amounts of thyrotropin-releasing hormone, a highly potent stimulator of α-MSH release. Recently, we have isolated and sequenced from the skin of the frog Phyllomedusa bicolor-a novel peptide named skin peptide tyrosine tyrosine (SPYY), which exhibits 94% similarity with PYY from the frog Rana ridibunda. For concentrations ranging from 5 × 10−10 to 10−7 M, SPYY induces a dose-related inhibition of α-MSH secretion. At a dose of 10−7 M, SPYY totally abolished α-MSH release. These data strongly suggest the existence of a regulatory loop between the pars intermedia of the pituitary and the skin in amphibians.