title: Extrinsic ghrelin in the paraventricular nucleus increases small intestinal motility in rats by activating central growth hormone secretagogue and enteric cholinergic receptors.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Gastroenterology, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China; Shannxi Provincial Key Laboratory of Gastrointestinal Motility Disorders, Xi'an 710004, China; Shannxi Provincial Clinical Research Center of Gastrointestinal Diseases, Xi'an 710004, China. Electronic address: wangyaneryuan@163.com.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China; Shannxi Provincial Key Laboratory of Gastrointestinal Motility Disorders, Xi'an 710004, China; Shannxi Provincial Clinical Research Center of Gastrointestinal Diseases, Xi'an 710004, China.
authors.forename: Fenrong
authors.initials: F
authors.lastname: Chen
authors.affiliation: Department of Gastroenterology, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China; Shannxi Provincial Key Laboratory of Gastrointestinal Motility Disorders, Xi'an 710004, China; Shannxi Provincial Clinical Research Center of Gastrointestinal Diseases, Xi'an 710004, China.
authors.forename: Haitao
authors.initials: H
authors.lastname: Shi
authors.affiliation: Department of Gastroenterology, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China; Shannxi Provincial Key Laboratory of Gastrointestinal Motility Disorders, Xi'an 710004, China; Shannxi Provincial Clinical Research Center of Gastrointestinal Diseases, Xi'an 710004, China.
authors.forename: Jiong
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Department of Gastroenterology, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China; Shannxi Provincial Key Laboratory of Gastrointestinal Motility Disorders, Xi'an 710004, China; Shannxi Provincial Clinical Research Center of Gastrointestinal Diseases, Xi'an 710004, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Gastroenterology, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China; Shannxi Provincial Key Laboratory of Gastrointestinal Motility Disorders, Xi'an 710004, China; Shannxi Provincial Clinical Research Center of Gastrointestinal Diseases, Xi'an 710004, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Qin
authors.affiliation: Department of Gastroenterology, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China; Shannxi Provincial Key Laboratory of Gastrointestinal Motility Disorders, Xi'an 710004, China; Shannxi Provincial Clinical Research Center of Gastrointestinal Diseases, Xi'an 710004, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D005769:Gastrointestinal Motility / Q000187:drug effects*; D015870:Gene Expression; D054439:Ghrelin / Q000494:pharmacology*; D007421:Intestine, Small / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D009478:Neuropeptide Y / Q000187:drug effects; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects* / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000187:drug effects / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D054440:Receptors, Ghrelin / Q000819:agonists*; D015398:Signal Transduction
chemical_list: D054439:Ghrelin; D018727:Muscarinic Antagonists; D009478:Neuropeptide Y; D016760:Proto-Oncogene Proteins c-fos; D054440:Receptors, Ghrelin
keywords: Brain–gut axis; Ghrelin; Growth hormone secretagogue receptor; Interdigestive myoelectric complex; Paraventricular nucleus; c-Fos