Developmental Origins of Functional Dyspepsia-Like Gastric Hypersensitivity in Rats

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 (TNBS); 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 (PND) 10 caused an aberrant increase of corticosterone on PND 15 and induced GHS in adult life. We called these FD-like rats. Inhibition of glucocorticoid receptors following neonatal insult blocked the induction of GHS in adult rats. The aberrant increase of plasma corticosterone in neonates elevated the plasma concentration of norepinephrine, nerve growth factor (NGF) in the gastric fundus muscularis externae, brain-derived neurotrophic factor (BDNF) in the thoracic dorsal root ganglia (DRG) and spinal cord, and downregulated Kv1.1 mRNA in thoracic DRG 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, NGF or BDNF in FD-like rats suppressed GHS. The intrathecal administration of small interfering RNAs against Kv1.1 increased GHS in naïve rats. Conclusion 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.

Protein Kinase C Mediates the Corticosterone-induced Sensitization of Dorsal Root Ganglion Neurons Innervating the Rat Stomach

“…This implies that the acute stress causes visceral responses more often and earlier than somatic responses. Consistent with previous studies that stress led to colonic hypersensitivity 41,42 and functional dyspepsia-like gastric hypersensitivity in rats, 7 which was most likely mediated by stress hormones such as CORT and epinephrine, we demonstrated for the first time that CORT injection induced gastric hypersensitivity in normal rats. However, the detailed mechanisms of systematic application CORT are not well understood.…”

“…A growing body of evidence demonstrates that physical or mental distress alters gut immunity and modulates the processing of incoming sensory signals by the brain, thus leading to a potentiation of sensory signals and aberrant visceral pain perception. [5][6][7][8] Corticosterone (CORT), one of the most important stress hormones, plays complex effects in neurological diseases. 9,10 A recent report showed that neonatal colonic chemical irritation with acetic acid produced FD-like gastric hypersensitivity and that inhibition of glucocorticoid receptors (GRs) during neonatal insult suppressed gastric hypersensitivity in adult rats.…”

“…9,10 A recent report showed that neonatal colonic chemical irritation with acetic acid produced FD-like gastric hypersensitivity and that inhibition of glucocorticoid receptors (GRs) during neonatal insult suppressed gastric hypersensitivity in adult rats. 7 In addition, chronic psychological stress increased CORT levels by activation of hypothalamic-pituitary-adrenal (HPA) axis, thus increasing the perception of visceral pain. 11 These data strongly indicate that CORT induced by physical or/and psychological stress is involved in chronic visceral hypersensitivity.…”

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…This hypothesis was recently tested in a rat model of FD. Adult rats subjected to inflammatory insult by intracolonic TNBS administration as neonates were reported to develop FD-like gastric hypersensitivity with no apparent involvement of TRPA1 (Winston and Sarna, 2013). In this context, it is worth mentioning that a combination of caraway and peppermint oil attenuates postinflammatory visceral hyperalgesia in rats .…”

Gut Inflammation: More Than a Peripheral Annoyance

“…This model induces long-term sensitization of GI afferents by inducing acute colonic inflammation at a key period in rat neonatal development [6]. Previously, Winston and Sarna reported that acute neonatal colonic inflammation induces long-term dysregulation of the sympatho-adrenal medullary axis in adult rats [7]. As adults, increased baseline circulating norepinephrine is linked to increased nerve growth factor expression in the gastric fundus and increased brain-derived neurotrophic factor in cells of the thoracic dorsal root ganglia.…”