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



## VSsupport (Feb 12, 2008)

[TD]
*Modulation of Gastrointestinal Function by MuDelta, a mixed Mu Opioid Receptor Agonist/Delta Opioid Receptor Antagonist.*

Br J Pharmacol. 2012 Jun 5;

Authors: Wade PR, Palmer JM, McKenney S, Kenigs V, Chevalier K, Moore BA, Mabus JR, Saunders PR, Wallace NH, Schneider CR, Kimball ES, Breslin HJ, He W, Hornby PJ

Abstract
Background & Purpose. Loperamide 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 constipation. We tested whether modulating µOR agonism with Î´OR 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 µOR agonist and high affinity Î´OR antagonist. Reference compounds, MuDelta and loperamide were assessed in ex vivo and in vivo experiments as follows: in guinea pig intestinal smooth muscle contractility, mouse intestinal epithelial ion transport, and upper GI transit, entire GI transit or fecal output in novel environment stressed mice, or four weeks after intracolonic mustard oil (post-inflammatory). Colonic Î´OR immunoreactivity was quantified. Key Results:Î´OR antagonism opposed µOR 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 Î´OR expression in colonic epithelial cells. In stressed mice, MuDelta normalized GI transit and fecal 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: Mixed µOR agonism/Î´OR antagonist normalizes, but does not prevent, perturbed GI transit over a wide dose-range in mice. These data supported the subsequent assessment MuDelta in a Clinical Phase II trial in patients with diarrhea-predominant irritable bowel syndrome. © 2012 Janssen R & D, LLC. British Journal of Pharmacology © 2012 The British Pharmacological Society.

PMID: 22671931 [PubMed - as supplied by publisher]

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