Developmental origins of functional dyspepsia-like gastric hypersensitivity in rats

John H. Winston, Sushil K. Sarna

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

Background & Aims: Gastric hypersensitivity (GHS) contributes to epigastric pain in patients with functional dyspepsia (FD); the etiology and cellular mechanisms of this dysfunction remain unknown. We investigated whether inflammatory insult to the colons of neonatal rats induced GHS in adult life. Methods: We used cellular, molecular, and in vivo approaches to investigate the mechanisms of GHS in adult rats subjected to neonatal colonic insult by intraluminal administration of trinitrobenzene sulfonic acid; controls received saline. Six to 8 weeks later, rats were evaluated for GHS and tissue was collected for molecular experiments. Results: Inflammatory insult to the colon on post-natal day 10 caused an aberrant increase of corticosterone on post-natal day 15 and induced GHS in adult life. We called these FD-like rats. Inhibition of glucocorticoid receptors after neonatal insult blocked the induction of GHS in adult rats. The aberrant increase of plasma corticosterone in neonates increased the plasma concentration of norepinephrine, nerve growth factor in the gastric fundus muscularis externae, brain-derived neurotrophic factor in the thoracic dorsal root ganglia and spinal cord, and down-regulated K v1.1 messenger RNA in thoracic dorsal root ganglia without affecting the expression of Kv1.4, Nav1.8, TrpA1, TrpV1, or P2X3 in FD-like rats. Inhibition of glucocorticoid receptors during neonatal insult or the inhibition of adrenergic receptors, nerve growth factor, or brain-derived neurotrophic factor in FD-like rats suppressed GHS. The intrathecal administration of small interfering RNAs against Kv1.1 increased GHS in naive rats. Conclusions: Inflammatory insult to the colons of rat pups leads to GHS in adult life. GHS is caused by altered expression of genes encoding neurotrophins and ion channels, and altered activity of the sympathetic nervous system.

Original languageEnglish (US)
Pages (from-to)570-579.e3
JournalGastroenterology
Volume144
Issue number3
DOIs
StatePublished - Mar 2013

Keywords

  • Abdominal Pain
  • Early Life Insult
  • Functional Bowel Disorders
  • Visceral Hypersensitivity

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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