Key Points• Understanding conditions of gastrointestinal dysmotility and impaired GI-transit requires accurate noninvasive techniques to monitor the precise location of ingested content.• We demonstrate a non-invasive high resolution X-ray imaging technique to track transit of solid material in vivo, under two specific pharmacological treatment conditions.• Our data indicate GI tract region-specific effects of the modulatory drugs on transit of contents.• We provide evidence that loperamide slows stomach emptying and GI transit, and that prucalopride increases stomach emptying and accelerates colonic transit in aged rats. AbstractBackground Dysmotility in the gastrointestinal (GI) tract often leads to impaired transit of luminal contents leading to symptoms of diarrhea or constipation. The aim of this research was to develop a technique using high resolution X-ray imaging to study pharmacologically induced aged rat models of chronic GI dysmotility that mimic accelerated transit (diarrhea) or constipation. The 5-hydroxytryptamine type 4 (5-HT 4 ) receptor agonist prucalopride was used to accelerate transit, and the opioid agonist loperamide was used to delay transit. Methods Male rats (18 months) were given 0, 1, 2, or 4 mg/kg/day prucalopride or loperamide (in dimethyl sulfoxide, DMSO) for 7 days by continuous 7-day dosing. To determine the GI region-specific effect, transit of six metallic beads was tracked over 12 h using high resolution X-ray imaging. An established rating scale was used to classify GI bead location in vivo and the distance beads had propagated from the caecum was confirmed postmortem. Key Results Loperamide (1 mg/kg) slowed stomach emptying and GI transit at 9 and 12 h. Prucalopride (4 mg/kg) did not significantly alter GI transit scores, but at a dose of 4 mg/kg beads had moved significantly more distal than the caecum in 12 h compared to controls. Conclusions & Inferences We report a novel high-resolution, non-invasive, X-ray imaging technique that provides new insights into GI transit rates in live rats. The results demonstrate that loperamide slowed overall transit in aged rats, while prucalopride increased stomach emptying and accelerates colonic transit.

Beta-casomorphin-5 (βCM-5) is a milk-derived bioactive peptide that slows gastro-intestinal transit (GIT) in vivo and blocks the peristaltic reflex in the guinea pig colon in vitro. We wanted to establish an in vitro model system in which effects of dairy-derived substances containing opioid peptides on intestinal motility can be assessed and used to predict in vivo outcomes. Because βCM-5 is an opioid agonist that acts on enteric neurons, we used this substance to compare two different isolated colonic tissue preparations to determine which would more closely mimic the in vivo response previously reported in the literature. We compared and characterized the effects of βCM-5 on spontaneous contractions in isolated segments of distal colon (1 cm length) compared with propagating contractions along the isolated intact large intestine (22 cm length). In short segments of distal colon, βCM-5 increased the tension and frequency of spontaneous contractions in a concentration-dependent manner. At 20 μM βCM-5 tension increased by 71 ± 17% and the frequency doubled (n = 9), effects inhibited by naloxone (n = 7) and therefore mediated by opioid receptors. In contrast 20 μM βCM-5 disrupted propagating contractions in the large intestine preparation. At 20 μM βCM-5 reduced the proportion of contractions initiated in the proximal colon reaching the rectum by 83 ± 11% (n = 5) and this effect was also inhibited by naloxone, consistent with altered GIT reported in vivo. Our results demonstrate that the isolated whole large intestine provides an ideal preparation that mimics the reduced propagation of GIT in vivo in response to an opioid agonist, whereas short colon segments did not. The findings of the current study reveal that preserving large segments of intact large intestine, and hence intact enteric neural circuitry provides an ideal in vitro model to investigate the effect of opioid receptor modulators on intestinal transit.

Diarrhea is caused by factors that alter absorption and secretion of water and ions across the intestinal epithelium and disrupt motility. Parasitic infection, stress, poor nutrition, and exposure to plant or fungal toxins predispose livestock to noninfectious diarrhea. This is more prevalent in sheep that graze pastures infected with wild-type endophytic fungus, suggesting the involvement of fungal alkaloids. These increase smooth muscle contraction: ergovaline/ergotamine (ergot alkaloid) activates serotonin (5-HT) receptors, and lolitrem B (indole diterpene) inhibits large-conductance Ca2+-activated K+ (BK) channels. Because of their separate mechanisms of action the objective of this study was to investigate whether they act synergistically to increase smooth muscle contraction. Effects of ergotamine (1 µM) and lolitrem B (0.1 µM) on the tension and frequency of spontaneous contractions were investigated in a longitudinal preparation of isolated distal colon. The compounds were dissolved in 0.1% dimethyl sulfoxide (DMSO) and applied separately or together for 1 h. Ergotamine increased contractile tension compared to the pretreatment control (P<0.01) and produced a short-lived increase in frequency (P<0.001). Lolitrem B increased contractile tension (P<0.05) but had no effect on frequency. When applied together, the contractile tension was greater than the sum of the compounds applied separately (P<0.05). The frequency of contractions was increased (P<0.05) but was not significantly different from that for ergotamine alone. The increased contractile tension when both compounds were applied together indicates that ergotamine and lolitrem B acted synergistically to increase smooth muscle contraction, suggesting that they would alter motility in vivo.

Goat and cow milk share similar protein and lipid content, yet goat milk forms softer curds during stomach digestion. This has been assumed to hasten gastric emptying (GE) for goat...