Journal article
Modulation of gastrointestinal function by MuDelta, a mixed mu opioid receptor agonist/mu opioid receptor antagonist
British journal of pharmacology, v 167(5), pp 1111-1125
Nov 2012
PMID: 22671931
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
BACKGROUND & PURPOSE Loperamide is a selective mu opioid receptor agonist acting locally in the gastrointestinal (GI) tract as an effective anti-diarrhoeal but can cause constipation. We tested whether modulating mu opioid receptor agonism with d opioid receptor antagonism, by combining reference compounds or using a novel compound (MuDelta), could normalize GI motility without constipation. EXPERIMENTAL APPROACH MuDelta was characterized in vitro as a potent mu opioid receptor agonist and high-affinity d opioid receptor antagonist. Reference compounds, MuDelta and loperamide were assessed in the following ex vivo and in vivo 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-inflammatory). Colonic d opioid receptor immunoreactivity was quantified. KEY RESULTS d Opioid receptor antagonism opposed mu opioid receptor agonist inhibition of intestinal contractility and motility. MuDelta reduced intestinal contractility and inhibited neurogenically-mediated secretion. Very low plasma levels of MuDelta were detected after oral administration. Stress up-regulated d 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-inflammatory model. CONCLUSIONS AND IMPLICATIONS MuDelta normalizes, but does not prevent, perturbed GI transit over a wide dose-range in mice. These data support the subsequent assessment of MuDelta in a clinical phase II trial in patients with diarrhoea-predominant irritable bowel syndrome.
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Details
- Title
- Modulation of gastrointestinal function by MuDelta, a mixed mu opioid receptor agonist/mu opioid receptor antagonist
- Creators
- P. R. Wade - Johnson & JohnsonJ. M. Palmer - Johnson & JohnsonS. McKenney - Johnson & JohnsonV. Kenigs - Johnson & JohnsonK. Chevalier - Johnson & JohnsonB. A. Moore - Johnson & JohnsonJ. R. Mabus - Johnson & JohnsonP. R. Saunders - Johnson & JohnsonN. H. Wallace - Johnson & JohnsonC. R. Schneider - Johnson & JohnsonE. S. Kimball - Johnson & JohnsonH. J. Breslin - Johnson & JohnsonW. He - Johnson & JohnsonP. J. Hornby - Johnson & Johnson
- Publication Details
- British journal of pharmacology, v 167(5), pp 1111-1125
- Publisher
- Wiley
- Number of pages
- 15
- Grant note
- Patricia Andrade-Gordon
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:000309599400016
- Scopus ID
- 2-s2.0-84867314129
- Other Identifier
- 991021931775204721
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- Web of Science research areas
- Pharmacology & Pharmacy