Modulation of Gastrointestinal Function by MuDelta, a mixed Mu Opioid Receptor Agonist/Delta Opioid Receptor Antagonist

Abstract

Background & PurposeLoperamide is a selective mu (μ) opioid receptor (OR) agonist acting locally in the gastrointestinal (GI) tract as an effective anti‐diarrheal, but can result in ‘rebound’ constipation. We tested whether modulating μOR agonism with δOR antagonism, by combining reference compounds or using a novel compound (“MuDelta”), could normalize GI motility without constipation.Experimental approachMuDelta was characterized in vitro as a potent μOR agonist and high affinity δOR antagonist. Compounds were assessed in guinea pig intestinal smooth muscle contractility and mouse intestinal epithelial ion transport. Colonic δOR immunoreactivity was quantified. MuDelta and loperamide were evaluated for upper GI transit, entire GI transit or fecal output in novel environment stressed mice, or four weeks after intracolonic mustard oil.Key ResultsδOR antagonism opposed μOR agonism in isolated intestinal and in vivo motility assays. Stress up‐regulated δOR expression in colonic epithelial cells. MuDelta reduced contractility in intestinal tissue similar to combined μOR agonists and δOR antagonists, and inhibited neurogenically‐mediated secretion. Very low plasma levels of MuDelta were detected after oral administration. In stressed mice, MuDelta normalized GI transit and fecal output to control levels over a wide dose range up to 100 mg/kg p.o, whereas loperamide completely prevented these at 10 mg/kg. MuDelta also reduced upper GI transit in the post‐inflammatory model.Conclusions and ImplicationsMixed μOR agonism/δOR antagonism normalizes, but does not prevent, perturbed GI transit over a wide dose‐range in mice. These data support the assessment of MuDelta in clinical trials in patients with diarrhea‐predominant irritable bowel syndrome.