Central and peripheral mechanisms by which ghrelin regulates gut motility

Ghrelin is the recently discovered endogenous ligand for the growth hormone secretagogue receptor. This receptor had previously been characterized based on the stimulatory effect of synthetic peptides, enkephalin analogues, on growth hormone secretion by pituitary somatotrophs. Surprisingly, ghrelin is most abundant in the stomach, suggesting that it may have effects beyond the stimulation of growth hormone in the pituitary and that it is a new brain-gut peptide. There is now increasing evidence that ghrelin stimulates motor activity in the gastrointestinal tract. Thus ghrelin induces the migrating motor complex and accelerates gastric emptying. These are effects typical for motilin, the only peptide structurally related to ghrelin. Moreover, the receptors of both peptides are structurally related as well. The motor effects of ghrelin require rather high concentrations, while motilin at high concentrations stimulates growth hormone release. These data suggest cross-reactivity. However, in vitro binding and contractility studies in the rabbit, the classical model to study motilin agonists, show that ghrelin has very weak if any interaction with the motilin receptor. Similarly, in cell lines expressing the receptors for both peptides there is no evidence for cross-reactivity. This corresponds to the fact that the pharmacophore of both peptides is quite different. Therefore, the motor effects must be due to the stimulation of specific central or peripheral ghrelin receptors. In the guinea pig there is evidence from electrophysiology, immunohistochemistry and calcium imaging studies for ghrelin receptors on myenteric neurons. This provides the morphological basis for peripheral effects of ghrelin. In rats, ghrelin, but not motilin, enhances the response of muscle strips to electrical field stimulation by activating cholinergic pathways. In rabbits the opposite is true but some synthetic ghrelin agonists have weak effects which cannot be blocked by motilin antagonists. Apparently ghrelin is the functional equivalent of motilin in the rat, but in rabbits the motilin-ghrelin family may have yet unknown members. In vivo the effect of ghrelin can be blocked by vagotomy and there is evidence for ghrelin receptors on vagal afferents and in the nodose ganglion. Studies in the rat suggest that under physiological conditions circulating ghrelin does not activate the myenteric plexus, but is able to do so following vagotomy. Finally, centrally administered ghrelin also accelerates gastric emptying and ghrelin changes the activity of neurons of the central nuclei involved in signalling information from the gastrointestinal tract. It is concluded that ghrelin may affect gastrointestinal motility via specific ghrelin receptors located on myenteric, vagal and central neurons. Vagal and central pathways appear to be most important. The fact that ghrelin may reverse the effect of ileus on gastric emptying suggests that ghrelin agonists could find therapeutical application as prokinetics.