Methyl-orvinol—Dual activity opioid receptor ligand inhibits gastrointestinal transit and alleviates abdominal pain in the mouse models mimicking diarrhea-predominant irritable bowel syndrome

摘要

Highlights ? Diarrhea-predominant irritable bowel syndrome (IBS-D) is a chronic gastrointestinal disorder. ? Opioid receptors (ORs) maintain the homeostasis in the GI tract. ? ORs ligands are an attractive option for developing new drugs in IBS-D therapy. ? Methyl-orvinol is MOP receptor agonist and KOP receptor antagonist in the GI tract. ? Methyl-orvinol reduced abdominal pain in mouse models mimicking IBS-D symptoms. Abstract Background Diarrhea-predominant irritable bowel syndrome (IBS-D) is a functional disorder of the gastrointestinal (GI) tract. The major IBS-D symptoms include diarrhea, abdominal pain and discomfort. High density of opioid receptors (ORs) in the GI tract and their participation in the maintenance of GI homeostasis make ORs ligands an attractive option for developing new anti-IBS-D treatments. The aim of this study was to characterize the effect of methyl-orvinol on the GI motility and secretion and in mouse models mimicking symptoms of IBS-D. Methods In vitro , the effects of methyl-orvinol on electrical field stimulated smooth muscle contractility and epithelial ion transport were characterized in the mouse colon. In vivo , the following tests were used to determine methyl-orvinol effect on mouse GI motility: colonic bead expulsion, whole GI transit and fecal pellet output. An antinociceptive action of methyl-orvinol was assessed in the mouse model of visceral pain induced by mustard oil. Results Methyl-orvinol (10 ?10 to 10 ?6 M) inhibited colonic smooth muscle contractions in a concentration-dependent manner. This effect was reversed by naloxone (non-selective opioid antagonist) and β-funaltrexamine (selective MOP antagonist). Experiments with a selective KOP receptor agonist, U50488 revealed that methyl-orvinol is a KOP receptor antagonist in the GI tract. Methyl-orvinol enhanced epithelial ion transport. In vivo , methyl-orvinol inhibited colonic bead expulsion and prolonged GI transit. Methyl-orvinol improved hypermotility and reduced abdominal pain in the mouse models mimicking IBS-D symptoms. Conclusion Methyl-orvinol could become a promising drug candidate in chronic therapy of functional GI diseases such as IBS-D.