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We tested whether modulating \u00b5 opioid receptor agonism with \u03b4 opioid receptor antagonism, by combining reference compounds or using a novel compound (\u2018MuDelta\u2019), could normalize GI motility without constipation.<\/jats:p><jats:p><jats:bold>EXPERIMENTAL APPROACH<\/jats:bold>MuDelta was characterized<jats:italic>in vitro<\/jats:italic>as a potent \u00b5 opioid receptor agonist and high\u2010affinity \u03b4 opioid receptor antagonist. Reference compounds, MuDelta and loperamide were assessed in the following<jats:italic>ex vivo<\/jats:italic>and<jats:italic>in vivo<\/jats:italic>experiments: guinea pig intestinal smooth muscle contractility, mouse intestinal epithelial ion transport and upper GI tract transit, entire GI transit or faecal output in novel environment stressed mice, or four weeks after intracolonic mustard oil (post\u2010inflammatory). Colonic \u03b4 opioid receptor immunoreactivity was quantified.<\/jats:p><jats:p><jats:bold>KEY RESULTS<\/jats:bold>\u03b4 Opioid receptor antagonism opposed \u00b5 opioid receptor agonist inhibition of intestinal contractility and motility. MuDelta reduced intestinal contractility and inhibited neurogenically\u2010mediated secretion. Very low plasma levels of MuDelta were detected after oral administration. Stress up\u2010regulated \u03b4 opioid receptor expression in colonic epithelial cells. In stressed mice, MuDelta normalized GI transit and faecal output to control levels over a wide dose range, whereas loperamide had a narrow dose range. MuDelta and loperamide reduced upper GI transit in the post\u2010inflammatory model.<\/jats:p><jats:p><jats:bold>CONCLUSIONS AND IMPLICATIONS<\/jats:bold>MuDelta normalizes, but does not prevent, perturbed GI transit over a wide dose\u2010range in mice. These data support the subsequent assessment of MuDelta in a clinical phase II trial in patients with diarrhoea\u2010predominant irritable bowel syndrome.<\/jats:p>","DOI":"10.1111\/j.1476-5381.2012.02068.x","type":"journal-article","created":{"date-parts":[[2012,6,5]],"date-time":"2012-06-05T15:46:15Z","timestamp":1338911175000},"page":"1111-1125","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":117,"title":["Modulation of gastrointestinal function by MuDelta, a mixed \u00b5 opioid receptor agonist\/ \u00b5 opioid receptor 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