Tu1876 Chronic Stress-Induced Visceral Hyperalgesia: Evidence for Differential Effects of Lubiprostone on Tight Junction Protein Expression in the Colon

Abstract

Introduction: In humans, chronic psychological stress is associated with increased intestinal permeability and visceral hyperalgesia, which is recapitulated in the chronic intermittent water avoidance stress (WAS) rat model. Previously, we reported that WAS rats demonstrated increased intestinal permeability for macromolecules specifically in the colon, which correlated with reduced epithelial tight junction protein expression in the colon epithelium. Lubiprostone (Lub), a prostaglandin receptor agonist used to treat chronic constipation and IBS-C, has been shown to restore barrier function and epithelial tight junction protein expression in the ischemic porcine intestine. Hypothesis: Lub treatment ameliorates increased colon permeability and visceral hyperalgesia in the WAS rat model. Methods: Male Sprague Dawley rats were subjected to one hour of WAS for 10 consecutive days with or without oral administration of Lub. A 20 μg/kg/day dose of Lub was chosen based on a dose response study. On day 11, visceral motor response (VMR) to colorectal distention (CRD) or colon permeability were measured. Permeability was assayed by measuring plasma levels of the non-ionic molecule FITC-Dextran (4KDa), which was given by gavage at 400 mg/Kg. Distal colon tissue was used for Western blot analysis. Results: WAS was associated with increased colon permeability compared to controls in 7 of 14 rats (p = 0.0036) and a decrease in the level of the epithelial tight junction protein occludin (p < 0.05). Lub prevented the stress-induced increase in colon permeability (p = 0.01), as well as the decrease in occludin. WAS rats had a significant increase in pellet output over controls (p < 0.0001), however there were no significant difference in pellet output between Lub treated and untreated WAS rats. All WAS rats showed visceral hyperalgesia in response to CRD (60 mmHg, p < 0.0001) in comparison to controls. Lub treatment of WAS rats prevented visceral hyperalgesia in response to CRD for 7 out of 14 rats (p < 0.0001), whereas the other 7 had VMR to CRD levels equivalent to untreated WAS rats. Conclusion: Lub prevents WASassociated: 1) decrease in epithelial tight junction protein expression in a subset of rats that showed an increase in colon permeability and 2) hyperalgesia in a subset of rats, despite genetic homogeneity. We hypothesize that increased gut permeability and hyperalgesia in response to WAS are linked, and the differential effects of WAS on colon permeability and Lub treatment on visceral hyperalgesia reflects differences in epigenetic regulation of relevant target genes.