In rats, the peptide GHRP-6 (a ghrelin receptor agonist) speeds up how fast the stomach empties and moves food along, similar to the natural hormone ghrelin, while another peptide, motilin, does not have this effect. The effect is linked to activation of the gut's cholinergic (acetylcholine‑driven) nerves.

Ghrelin and motilin form a new family of structurally related peptides. We compared the gastroprokinetic effects of ghrelin, the ghrelin receptor agonist, growth hormone releasing peptide 6 (GHRP-6), and motilin in rats in vivo and in vitro. Ghrelin, GHRP-6 or motilin (10-150 microg/kg) were injected i.p. and the effects on gastric emptying and transit were measured after intragastric application of Evans blue. In antral and fundic strips the effect of motilin, ghrelin or GHRP-6 was studied during electrical field stimulation (EFS) in the absence and presence of N(G)-nitro-l-arginine methyl ester hydrochloride (l-NAME) (300 microM). Ghrelin and GHRP-6 but not motilin accelerated gastric emptying and transit in rats. Ghrelin was more potent than GHRP-6 and the dose-response relationship for ghrelin but not for GHRP-6 was bell-shaped. In fundic or antral strips, neural responses to EFS consisted of an on-relaxation that was reversed into a cholinergically mediated contraction by addition of the nitric oxide (NO)-synthase blocker, l-NAME. The post-stimulus off-contraction was cholinergically mediated. Under normal conditions, the ghrelin agonists reduced the on-relaxations in fundic strips and increased the cholinergic off-contractions in antral and fundic strips. The concentration response curves in muscle strips of the fundus were bell-shaped with maximal effects for ghrelin at 1.2 microM (on-responses) and 0.66 microM (off-responses) and for GHRP-6 at 0.50 microM (on-responses) and 0.26 microM (off-responses). No effects were observed with motilin between 1 nM and 0.1 microM. Studies in the presence of l-NAME confirmed the effect of the ghrelin agonists on cholinergic excitatory motor responses. No effects were observed with motilin under the different experimental conditions. The presence of growth hormone secretagogue receptor 1a transcripts in the strip preparations was confirmed by reverse transcriptase polymerase chain reaction (RT-PCR). Ghrelin and GHRP-6 but not motilin accelerate gastric emptying and transit by activating cholinergic excitatory pathways in the enteric nervous system in addition to the known vagal pathways.