title: Methyl-orvinol-Dual activity opioid receptor ligand inhibits gastrointestinal transit and alleviates abdominal pain in the mouse models mimicking diarrhea-predominant irritable bowel syndrome.
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 (10-10to 10-6M) 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.
  
  
  CONCLUSIONS
  Methyl-orvinol could become a promising drug candidate in chronic therapy of functional GI diseases such as IBS-D.
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Łódź, Poland.
authors.forename: Marta
authors.initials: M
authors.lastname: Zielińska
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Łódź, Poland.
authors.forename: Agata
authors.initials: A
authors.lastname: Jarmuż
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Łódź, Poland.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Wasilewski
authors.affiliation: Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom.
authors.forename: Gerta
authors.initials: G
authors.lastname: Cami-Kobeci
authors.affiliation: Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom.
authors.forename: Stephen
authors.initials: S
authors.lastname: Husbands
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Łódź, Poland. Electronic address: jakub.fichna@umed.lodz.pl.
authors.forename: Jakub
authors.initials: J
authors.lastname: Fichna
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology; D015746:Abdominal Pain / Q000188:drug therapy* / Q000209:etiology; D000700:Analgesics / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D003106:Colon / Q000187:drug effects / Q000378:metabolism; D003967:Diarrhea / Q000150:complications / Q000378:metabolism; D004195:Disease Models, Animal; D005769:Gastrointestinal Motility / Q000187:drug effects; D005772:Gastrointestinal Transit / Q000187:drug effects*; D043183:Irritable Bowel Syndrome / Q000150:complications / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D009270:Naloxone / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D011957:Receptors, Opioid / Q000378:metabolism*; D013797:Thebaine / Q000494:pharmacology
chemical_list: D000700:Analgesics; D000701:Analgesics, Opioid; D011957:Receptors, Opioid; D013797:Thebaine; D009270:Naloxone; D009271:Naltrexone; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; C024524:beta-funaltrexamine
keywords: Abdominal pain; GI motility; Methyl-orvinol; Opioid receptors; Orvinols