Sa2021 The Stress Hormone Urocortin 1 Induces Gastric Dysfunction by α2-Adrenergic Receptor-Mediated Decrease in Ghrelin Signal in Rats

Abstract

Background/Aim: Excessive stress in modern society is associated with development of functional dyspepsia, which presents with symptoms of epigastric pain, early satiety and postprandial fullness. The central neural peptides, members of the corticotropin-releasing factor family, play key roles in response to stress. We previously reported that urocortin1 (UCN1) suppressed feeding behavior in fasted rats through an α2-adrenergic receptor (α2AR) activation, which decreases ghrelin secretion (DDW 2014). However, the influence of UCN1 on gastrointestinal (GI) function remains unclear. To elucidate this, we investigated the changes in gastric emptying and GI motility in UCN1-treated rats. Methods: UCN1 (300 pmol/rat) or phosphate-buffered saline (PBS) were intracerebroventricularly (ICV) injected to Sprague-Dawley rats, and gastric emptying and plasma ghrelin levels 2 h after oral administration of test meal were measured. The α2-AR antagonist, yohimbine (5 mg/kg) 15 min before ICV were intraperitoneal(IP) administered to UCN1-treated rats. Furthermore, ghrelin (3 nmol/rat, intravenous (IV)) were administered to UCN1-treated rats. In another set of experiment, the effects of co-administration of rikkunshito (RKT; 1000 mg/kg, which is an endogenous ghrelin enhancer) and with the ghrelin receptor antagonist ([D-Lys3] GHRP-6; 4 μmol/kg IV) was investigated. GI motility was investigated to determine the effects of ghrelin or RKT to UCN1-treated rats using a strain gauge force transducer in free-moving condition. Results: UCN1-treated rats exhibited significantly delayed gastric emptying. Administration of yohimbine improved gastric emptying (UCN1: 22.9±6.5 %, UCN1+yohimbine: 58.5±7.6 %, p<0.05) and significantly increased plasma ghrelin levels (UCN1:47.2±3.6 fmol/mL, UCN1+yohimbine: 81.9±7.8 fmol/mL, p<0.05). Exogenous administration of ghrelin restored delayed gastric empting. Administration of RKT significantly prevented delayed gastric empting and decreased plasma ghrelin levels. The gastric function of RKT was blocked by co-administration of the ghrelin receptor antagonist. ICV injection of UCN1 decreased the amplitude of contraction in the stomach while increasing the amplitude in the duodenum. Motility index of the stomach, but not the duodenum, was significantly reduced by treatment with UCN1 (PBS: 92.1 ± 10.1%, UCN1: 62.8 ± 4.7%), which was improved by the administration of ghrelin or RKT (99.03 ± 7.95%, p<0.05). Conclusions UCN1-induced gastric motility dysfunction with decrease in plasma ghrelin levels wasmediated byα2-AR activation. Disturbance in endogenous ghrelin dynamics play an important role in the functional abnormality of the upper GI tract under stressful conditions.