title: Noninflammatory upregulation of nerve growth factor underlies gastric hypersensitivity induced by neonatal colon inflammation.
abstract: Gastric hypersensitivity is one of the key contributors to the postprandial symptoms of epigastric pain/discomfort, satiety, and fullness in functional dyspepsia patients. Epidemiological studies found that adverse early-life experiences are risk factors for the development of gastric hypersensitivity. Preclinical studies found that neonatal colon inflammation elevates plasma norepinephrine (NE), which upregulates expression of nerve growth factor (NGF) in the muscularis externa of the gastric fundus. Our goal was to investigate the cellular mechanisms by which NE upregulates the expression of NGF in gastric hypersensitive (GHS) rats, which were subjected previously to neonatal colon inflammation. Neonatal colon inflammation upregulated NGF protein, but not mRNA, in the gastric fundus of GHS rats. Western blotting showed upregulation of p110γ of phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K), phosphoinositide-dependent kinase-1 (PDK1), pAKT(Ser473), and phosphorylated 4E-binding protein (p4E-BP1)(Thr70), suggesting AKT activation and enhanced NGF protein translation. AKT inhibitor MK-2206 blocked the upregulation of NGF in the fundus of GHS rats. Matrix metalloproteinase 9 (MMP-9), the major NGF-degrading protease, was suppressed, indicating that NGF degradation was impeded. Incubation of fundus muscularis externa with NE upregulated NGF by modulating the protein translation and degradation pathways. Yohimbine, an α2-adrenergic receptor antagonist, upregulated plasma NE and NGF expression by activating the protein translation and degradation pathways in naive rats. In contrast, a cocktail of adrenergic receptor antagonists suppressed the upregulation of NGF by blocking the activation of the protein translation and degradation pathways. Our findings provide evidence that the elevation of plasma NE induces NGF expression in the gastric fundus.
authors.affiliation: Enteric Neuromuscular Disorders and Visceral Pain Center, Division of Gastroenterology and Hepatology, Department of Internal Medicine, The University of Texas Medical Branch at Galveston, Galveston, Texas; and.
authors.forename: Qingjie
authors.initials: Q
authors.lastname: Li
authors.affiliation: Enteric Neuromuscular Disorders and Visceral Pain Center, Division of Gastroenterology and Hepatology, Department of Internal Medicine, The University of Texas Medical Branch at Galveston, Galveston, Texas; and.
authors.forename: John H
authors.initials: JH
authors.lastname: Winston
authors.affiliation: Enteric Neuromuscular Disorders and Visceral Pain Center, Division of Gastroenterology and Hepatology, Department of Internal Medicine, The University of Texas Medical Branch at Galveston, Galveston, Texas; and Department of Neuroscience and Cell Biology, The University of Texas Medical Branch at Galveston, Galveston, Texas sksarna@utmb.edu.
authors.forename: Sushil K
authors.initials: SK
authors.lastname: Sarna
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases / Q000378:metabolism; D015746:Abdominal Pain / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D018674:Adrenergic Antagonists / Q000494:pharmacology; D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D002352:Carrier Proteins / Q000378:metabolism; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000378:metabolism; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D003106:Colon / Q000187:drug effects / Q000294:innervation / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D005748:Gastric Fundus / Q000187:drug effects / Q000294:innervation / Q000378:metabolism* / Q000503:physiopathology; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D020932:Nerve Growth Factor / Q000378:metabolism*; D009638:Norepinephrine / Q000097:blood*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D055550:Protein Stability; D059748:Proteolysis; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D014302:Trinitrobenzenesulfonic Acid; D015854:Up-Regulation
chemical_list: D018674:Adrenergic Antagonists; D002352:Carrier Proteins; C499526:Eif4ebp1 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; D014302:Trinitrobenzenesulfonic Acid; D020932:Nerve Growth Factor; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546765:Pik3cg protein, rat; D064413:3-Phosphoinositide-Dependent Protein Kinases; C578579:Pdpk1 protein, rat; D051057:Proto-Oncogene Proteins c-akt; D020780:Matrix Metalloproteinase 9; C572337:Mmp9 protein, rat; D009638:Norepinephrine
keywords: functional dyspepsia; neurotrophins; posttranscriptional upregulation; sympathetic activity