Extrinsic ghrelin in the paraventricular nucleus increases small intestinal motility in rats by activating central growth hormone secretagogue and enteric cholinergic receptors

Background/objectives: Ghrelin is a brain-gut peptide that regulates gastrointestinal (GI) motility. We hypothesized that the excitatory effect of ghrelin on the paraventricular nucleus (PVN) increases GI motility by activating the central growth hormone secretagogue receptor (GHSR) and central neuropeptide Y (NPY) signaling pathways, leading to increased enteric cholinergic activity.

Methods: Thirty-six male Sprague Dawley rats were maintained on duodenal catheterization and PVN cannulation. Small intestinal transit (SIT) was observed and rats were divided as follows: experimental animals received ghrelin injections in the PVN (0.03, 0.08, or 0.24 nM); 1 nM GHSR antagonist D-Lys3-GHRP6 alone; 1nM D-Lys3-GHRP6 before ghrelin injection in the PVN, respectively. Electrophysiologic parameters of the interdigestive myoelectric complex (IMC) were examined by administration of 0.24 nM ghrelin in the PVN after small intestinal electrode implantation and PVN cannulation. GI cholinergic pathway activation was analyzed after intravenous atropine administration. The involvement of central NPY signaling was evaluated by injecting an anti-NPY immunoglobulin (IgG) in the PVN. Neuronal expression of c-Fos in the brain and GI tract was examined using immunohistochemistry.

Results: Injection of ghrelin in the PVN dose-dependently accelerated SIT, and this excitatory effect was competitively inhibited by a GHSR antagonist. The excitatory effect of ghrelin on IMC activity was diminished by GHSR antagonism and NPY neutralization, as well as by blockade of peripheral muscarinic acetylcholine receptors. Extrinsic ghrelin significantly upregulated c-Fos expression in the PVN and other central nuclei, as well as in the enteric nervous plexuses of the stomach, duodenum, and proximal colon. The ghrelin-induced upregulation of central and enteric c-Fos expression was also dependent on central GHSR activation.

Conclusions: Ghrelin positively regulates GI motility by exciting both central and enteric neurons, including those of the PVN, by activating GHSR and NPY pathways, and peripheral muscarinic acetylcholine receptors.