title: Anti-inflammatory effect of dual nociceptin and opioid receptor agonist, BU08070, in experimental colitis in mice.
abstract: Endogenous opioid and nociceptin systems are widely distributed in the gastrointestinal tract where they seem to play a crucial role in maintaining the intestinal homeostasis. The aim of our study was to assess whether activation of nociceptin (NOP) and µ-opioid (MOP) receptors by a mixed NOP/MOP receptor agonist, BU08070, induces anti-inflammatory response in experimental colitis. The anti-inflammatory effect of BU08070 (1 mg/kg i.p.) was characterized in the mouse model of 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis, based on the assessment of the macroscopic and microscopic total damage scores and determination of myeloperoxidase (MPO) activity and TNF-α level in the colon. The effect of BU08070 on cell viability and NF-κB was characterized in THP-1 Blue cell line. The antinociceptive activity of BU08070 was examined in mustard oil-induced mouse model of abdominal pain. A potent anti-inflammatory effect of BU08070 (1 mg/kg i.p.) was observed as indicated by decrease in macroscopic damage score (1.88±0.39 vs. 5.19±0.43 units in TNBS alone treated mice), MPO activity (2.29±0.37 vs. 9.64±2.55 units) and TNF-α level in the colon (35.85±2.45 vs. 49.79±3.81 pg/ml). The anti-inflammatory effect of BU08070 was reversed by selective NOP and MOP receptor antagonists. BU08070 produced concentration-dependent inhibition of TNF-α and LPS-induced NF-κB activation. BU08070 exerted antinociceptive action in mice with experimental colitis. In conclusion, BU08070 significantly reduced the severity of colitis in TNBS-treated mice compared with controls. These results suggest that BU08070 is a potential therapeutic agent for inflammatory bowel diseases therapy.
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland.
authors.forename: Marta
authors.initials: M
authors.lastname: Zielińska
authors.affiliation: Department of Pharmaceutical Chemistry, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria.
authors.forename: Tanila
authors.initials: T
authors.lastname: Ben Haddou
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, Lodz, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Sałaga
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland.
authors.forename: Agata
authors.initials: A
authors.lastname: Jarmuż
authors.affiliation: Department of Gastroenterology, Faculty of Military Medicine, Medical University of Lodz, Lodz, Poland.
authors.forename: Milena
authors.initials: M
authors.lastname: Padysz
authors.affiliation: Department of Pathology, Faculty of Medicine, Medical University of Lodz, Lodz, Poland.
authors.forename: Radzisław
authors.initials: R
authors.lastname: Kordek
authors.affiliation: Department of Pharmaceutical Chemistry, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria.
authors.forename: Mariana
authors.initials: M
authors.lastname: Spetea
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, Lodz, Poland. Electronic address: jakub.fichna@umed.lodz.pl.
authors.forename: Jakub
authors.initials: J
authors.lastname: Fichna
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002047:Buprenorphine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D002460:Cell Line; D003092:Colitis / Q000139:chemically induced* / Q000188:drug therapy* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011957:Receptors, Opioid / Q000819:agonists* / Q000378:metabolism; D016896:Treatment Outcome; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity; D000094942:Nociceptin Receptor
chemical_list: D000893:Anti-Inflammatory Agents; C000595062:BU08070; D011957:Receptors, Opioid; D002047:Buprenorphine; D014302:Trinitrobenzenesulfonic Acid; D000094942:Nociceptin Receptor
keywords: Crohn's disease; Inflammatory bowel diseases; Mixed opioid agonists; Visceral pain