Combined blockade of both μ- and κ-opioid receptors prevents the acute orexigenic action of agouti-related protein

Agouti-related protein (AgRP) is an endogenous antagonist at the melanocortin 3 and 4 receptor in the hypothalamus. Central administration of AgRP produces a robust increase in food intake, and this effect can be blocked by administration of nonspecific opioid receptor antagonist. Such results implicate opioid receptors as critical to mediating the effects of AgRP. To determine which opioid receptor subtype is critical, we first determined the highest i3vt (administered into the third ventricle) dose of two specific opioid antagonists, nor-Binaltorphine or beta-funaltrexamine, that did not influence food intake on their own. Then, rats were pretreated with either of these two antagonists before i3vt AgRP and access to a high-fat diet. For neither the kappa- nor the mu-specific antagonist was there any effect to block the effects of AgRP on food intake. However, administration of both the kappa- and mu-receptor antagonists does significantly reduce the effect of AgRP. The current results implicate opioid receptors as critical downstream mediators of the potent effects of AgRP to increase food intake but indicate that either mu- or kappa-receptor activation is sufficient for AgRP's effect.