The effects on food intake of the N-acetylation of MSH and beta-endorphin have been examined following their injection into the third ventricle. Desacetyl-MSH and alpha-MSH were injected into fasted rats, and beta-endorphin and N-acetyl-beta-endorphin into fed rats. Desacetyl-MSH had no effect on food intake following ICV injection into food-deprived rats at any dose between 100 and 2500 pmoles. Alpha-MSH, the N-acetylated form of MSH, on the other hand, showed a highly significant inhibition of food intake in food-deprived rats with doses of 100 and 250 pmoles but no effect with the higher doses. With beta-endorphin, there was a dose-related biphasic effect. One hour after injection of beta-endorphin (2500 pmole) food intake was inhibited whereas the lowest dose, 100 pmole, significantly stimulated it. By 3 hours, the 2 lowest doses of beta-endorphin both significantly stimulated food intake, but the highest dose remained inhibitory. By 6 hours all doses of beta-endorphin stimulated food intake compared to the vehicle-treated animals. In contrast, N-acetylation of beta-endorphin eliminated all effects on food intake following injection into the third ventricle. These data suggest that N-acetylation of products formed by the processing of POMC can markedly alter their biological properties.