Melanin-concentrating hormone (MCH) and α-melanocyte-stimulating hormone (α-MSH) demonstrate opposite actions on skin coloration in teleost fish. Both peptides are present in the mammalian brain, although their specific physiological roles remain largely unknown. In this study, we examined the interactions between MCH and α-MSH after intracerebroventricular administration in rats. MCH increased food intake in a dose-dependent manner and lowered plasma glucocorticoid levels through a mechanism involving ACTH. In contrast, α-MSH decreased food intake and increased glucocorticoid levels. MCH, at a twofold molar excess, antagonized both actions of α-MSH. α-MSH, at a threefold molar excess, blocked the orexigenic properties of MCH. MCH did not block α-MSH binding or the ability of α-MSH to induce cAMP in cells expressing either the MC3 or MC4 receptor, the principal brain α-MSH receptor subtypes. These data suggest that MCH and α-MSH exert opposing and antagonistic influences on feeding behavior and the stress response and may function in a coordinate manner to regulate metabolism through a novel mechanism mediated in part by an MCH receptor.