Disodium Cromoglycate Reverses Colonic Visceral Hypersensitivity and Influences Colonic Ion Transport in a Stress-Sensitive Rat Strain

Abstract

The interface between psychiatry and stress-related gastrointestinal disorders (GI), such as irritable bowel syndrome (IBS), is well established, with anxiety and depression the most frequently occurring comorbid conditions. Moreover, stress-sensitive Wistar Kyoto (WKY) rats, which display anxiety- and depressive-like behaviors, exhibit GI disturbances akin to those observed in stress-related GI disorders. Additionally, there is mounting preclinical and clinical evidence implicating mast cells as significant contributors to the development of abdominal visceral pain in IBS. In this study we examined the effects of the rat connective tissue mast cell (CTMC) stabiliser, disodium cromoglycate (DSCG) on visceral hypersensitivity and colonic ion transport, and examined both colonic and peritoneal mast cells from stress-sensitive WKY rats. DSCG significantly decreased abdominal pain behaviors induced by colorectal distension in WKY animals independent of a reduction in colonic rat mast cell mediator release. We further demonstrated that mast cell-stimulated colonic ion transport was sensitive to inhibition by the mast cell stabiliser DSCG, an effect only observed in stress-sensitive rats. Moreover, CTMC-like mast cells were significantly increased in the colonic submucosa of WKY animals, and we observed a significant increase in the proportion of intermediate, or immature, peritoneal mast cells relative to control animals. Collectively our data further support a role for mast cells in the pathogenesis of stress-related GI disorders.

Early‐life stress selectively affects gastrointestinal but not behavioral responses in a genetic model of brain–gut axis dysfunction

“…B). We have previously reported threshold responses ranging from 35 mmHg to 50–60 mmHg in SD rats, and a total number of pain behaviors from 4 to 6 . We do, however, acknowledge that 60 mmHg is at the higher end of this range, but not dissimilar to our previous observations .…”

“…We have previously reported threshold responses ranging from 35 mmHg to 50–60 mmHg in SD rats, and a total number of pain behaviors from 4 to 6 . We do, however, acknowledge that 60 mmHg is at the higher end of this range, but not dissimilar to our previous observations . This increased sensitivity to visceral pain was further enhanced by exposure to early‐life stress in WKY‐MS animals ( p < 0.01 to p < 0.001, Fig.…”

“…Given the comorbidity between psychiatric disorders and IBS, it is not surprising that rodent models of depression and anxiety have proven to be useful tools in investigating this stress‐related disorder . In particular, the Wistar Kyoto (WKY) rat, first reported to display an enhanced response to colorectal distension (CRD) by Greenwood‐Van Meerveld et al ., has subsequently proven to be a useful animal model in which to interrogate the pathophysiology of abdominal visceral pain . Moreover, WKY rats have marked elevations in stress‐ and depression‐associated changes when compared to Sprague–Dawley (SD) rats, the strain most commonly used as a control comparator.…”

“…7,8 In particular, the Wistar Kyoto (WKY) rat, first reported to display an enhanced response to colorectal distension (CRD) by Greenwood-Van Meerveld et al, 9 has subsequently proven to be a useful animal model in which to interrogate the pathophysiology of abdominal visceral pain. [10][11][12][13][14] Moreover, WKY rats have marked elevations in stress-and depression-associated changes when compared to Sprague-Dawley (SD) rats, the strain most commonly used as a control comparator. These include heightened behavioral responses to stress, [15][16][17][18][19] an exaggerated increase in adrenocorticotropic hormone and corticosterone levels.…”

Irritable bowel syndrome: new and emerging treatments

“…128 Mast cell stabilizers Because of the putative role of mast cells in the pathophysiology of IBS, disodium cromoglycate, a mast cell stabilizer, is being evaluated in an animal model of IBS and was recently found to significantly decrease abdominal pain behaviors induced by colorectal distension compared with a saline control (P<0.05). 129 Furthermore, this molecule also inhibited mast cell stimulated colonic ion transport, an effect seen only in stress sensitive rats. A randomized trial of ketotifen seemed to increase the sensory threshold for discomfort during a rectal barostat in patients with IBS and visceral hypersensitivity.…”