title: Novel mixed NOP/MOP agonist BU08070 alleviates pain and inhibits gastrointestinal motility in mouse models mimicking diarrhea-predominant irritable bowel syndrome symptoms.
abstract: The opioid and nociceptin systems play a crucial role in the maintenance of homeostasis in the gastrointestinal (GI) tract. The aim of this study was to characterize the effect of BU08070, a novel mixed MOP/NOP agonist, on mouse intestinal contractility in vitro and GI motility in vivo in physiological conditions and in animal models mimicking symptoms of irritable bowel syndrome (IBS), including diarrhea and abdominal pain. The effect of BU08070 on muscle contractility in vitro was characterized in the ileum and colon. To assess the effect of BU08070 in vivo, the following parameters were assessed: whole GI transit, gastric emptying, geometric center, colonic bead expulsion, fecal pellet output and time to castor oil-induced diarrhea. The antinociceptive activity of BU08070 was characterized in the mustard oil (MO)-induced abdominal pain model and the writhing test, alone and in the presence of MOP and NOP antagonists. in vitro, BU08070 (10(-10)-10(-6) M) inhibited colonic and ileal smooth muscle contractions in a concentration-dependent manner. in vivo, BU08070 prolonged the whole GI transit and inhibited colonic bead expulsion. The antitransit and antidiarrheal effects of BU08070 were observed already at the dose of 0.1 mg/kg (i.p.). BU08070 reversed hypermotility and reduced pain in mouse models mimicking IBS-D symptoms. Our results suggest that BU08070 has a potential of becoming an efficient drug in IBS-D therapy. Here we also validate mixed NOP/MOP receptor targeting as possible future treatment of functional GI diseases.
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland.
authors.forename: Marta
authors.initials: M
authors.lastname: Sobczak
authors.affiliation: Department of Pharmacy and Pharmacology, University of Bath, Bath, UK.
authors.forename: Gerta
authors.initials: G
authors.lastname: Cami-Kobeci
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Sałaga
authors.affiliation: Department of Pharmacy and Pharmacology, University of Bath, Bath, UK.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Husbands
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland. Electronic address: jakub.fichna@umed.lodz.pl.
authors.forename: Jakub
authors.initials: J
authors.lastname: Fichna
mesh_terms: D015746:Abdominal Pain / Q000139:chemically induced / Q000188:drug therapy*; D000701:Analgesics, Opioid / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D002047:Buprenorphine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D002368:Castor Oil; D003106:Colon / Q000187:drug effects / Q000502:physiology; D003967:Diarrhea / Q000139:chemically induced / Q000188:drug therapy*; D004195:Disease Models, Animal; D005746:Gastric Emptying / Q000187:drug effects; D005769:Gastrointestinal Motility / Q000187:drug effects; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D043183:Irritable Bowel Syndrome / Q000188:drug therapy*; D008297:Male; D008807:Mice, Inbred BALB C; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009149:Mustard Plant; D010938:Plant Oils; D011957:Receptors, Opioid / Q000819:agonists / Q000502:physiology; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000502:physiology; D000094942:Nociceptin Receptor
chemical_list: D000701:Analgesics, Opioid; C000595062:BU08070; D010938:Plant Oils; D011957:Receptors, Opioid; D017450:Receptors, Opioid, mu; D002047:Buprenorphine; D002368:Castor Oil; C027793:mustard oil; D000094942:Nociceptin Receptor
keywords: Abdominal pain; Buprenorphine; Gastrointestinal motility; Irritable bowel syndrome; Mixed agonist