Differential orexigenic effects of hexarelin and its analogs in the rat hypothalamus: Indication for multiple growth hormone secretagogue receptor subtypes

We have previously reported that hexarelin and some of its analogs, includi ng EP 50885, stimulated GH secretion and feeding after systemic administrat ion in the rat, whereas EP 40904 selectively stimulated food intake and EP 40737 only GH release. The precise mechanism of growth hormone-releasing pe ptides (GHRPs) actions is still unclear, but the integrity of the arcuate n ucleus of the hypothalamus (ARC) appears crucial for their endocrine effect s. To better characterize the site(s) and mechanisms(s) of the orexigenic a ction of GHRPs, we have investigated their effects after infusion into the arcuate, paraventricular, ventromedial and medial preoptic areas of the hyp othalamus. Food intake was measured for 60 min following injection of the t est compound (2 mug/ rat). Hexarelin, EP 40904 and EP 50885 had significant orexigenic effects after injection into the ARC. A specific NPY antagonist significantly inhibited the effect of hexarelin, whereas a GHRH antagonist was ineffective. In the paraventricular nucleus, only EP 50885 stimulated feeding, whereas all peptides were ineffective in the ventromedial nucleus and medial preoptic area. Taken altogether, these results demonstrate that GHRPs are endowed with site-specific orexigenic actions and that endogenous NPV, but not GHRH, mediates these effects. The additional orexigenic actio n of EP 50885 in the paraventricular nucleus suggests the existence of a GH RP receptor subtype different from the already cloned one. Copyright (C) 20 00 S. Karger AG,Basel.