Wang Yan, Chen Fenrong, Shi Haitao, Jiang Jiong, Li Hong, Qin Bin, Li Yong
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.
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.
Peptides. 2015 Dec;74:43-9. doi: 10.1016/j.peptides.2015.09.009. Epub 2015 Sep 30.
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.
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.
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.
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.
背景/目的：胃饥饿素是一种调节胃肠（GI）动力的脑肠肽。我们假设胃饥饿素对室旁核（PVN）的兴奋作用通过激活中枢生长激素促分泌素受体（GHSR）和中枢神经肽Y（NPY）信号通路来增加胃肠动力，从而导致肠胆碱能活性增加。
36只雄性Sprague Dawley大鼠进行十二指肠插管和PVN插管。观察小肠转运（SIT）情况，并将大鼠分为以下几组：实验动物在PVN注射胃饥饿素（0.03、0.08或0.24 nM）；单独注射1 nM GHSR拮抗剂D-Lys3-GHRP6；在PVN注射胃饥饿素前分别注射1 nM D-Lys3-GHRP6。在植入小肠电极和PVN插管后，通过在PVN注射0.24 nM胃饥饿素检查消化间期肌电复合波（IMC）的电生理参数。静脉注射阿托品后分析胃肠胆碱能途径的激活情况。通过在PVN注射抗NPY免疫球蛋白（IgG）评估中枢NPY信号通路的参与情况。使用免疫组织化学检查脑和胃肠道中c-Fos的神经元表达。
在PVN注射胃饥饿素剂量依赖性地加速SIT，并且这种兴奋作用被GHSR拮抗剂竞争性抑制。GHSR拮抗、NPY中和以及外周毒蕈碱型乙酰胆碱受体阻断均减弱了胃饥饿素对IMC活性的兴奋作用。外源性胃饥饿素显著上调PVN和其他中枢核以及胃、十二指肠和近端结肠肠神经丛中c-Fos的表达。胃饥饿素诱导的中枢和肠c-Fos表达上调也依赖于中枢GHSR激活。
胃饥饿素通过激活GHSR和NPY途径以及外周毒蕈碱型乙酰胆碱受体，兴奋中枢和肠神经元（包括PVN神经元），从而对胃肠动力产生正向调节作用。
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