title: Anti-inflammatory action of a novel orally available peptide 317 in mouse models of inflammatory bowel diseases.
abstract: BACKGROUND
  The endogenous opioid system constitutes an attractive target in the treatment of GI disorders, including inflammatory bowel diseases (IBD). The aim of our study was to characterize the anti-inflammatory and antinociceptive effect of P-317, a novel cyclic analog of opioid peptide morphiceptin, in animal models of IBD.
  
  
  METHODS
  The anti-inflammatory effect of P-317 after intraperitoneal (ip) and oral (po) administration was assessed in two mouse models of IBD - Crohn's disease, induced by intracolonic instillation of trinitrobenzenesulfonic acid (TNBS) and ulcerative colitis, induced by addition of dextran sodium sulfate (DSS) into drinking water. The antinociceptive action of P-317 was characterized in mice with acute colitis using mustard oil-induced pain test. Real time RT PCR was used to assess semiquantitatively the expression of IL-1β and TNF-α mRNA in mouse colonic samples. To translate our results to clinical conditions, MOP and KOP mRNA were quantified in human colonic biopsies from IBD patients.
  
  
  RESULTS
  P-317 (0.1mg/kg, ip and 1mg/kg, po) alleviated colonic inflammation in TNBS- and DSS-treated mice in the opioid receptor-dependent manner. The anti-inflammatory effect of P-317 was associated with the decrease in mRNA expression of proinflammatory cytokines. The antinociceptive effect of P-317 was observed after ip and po administration in mice with acute colitis.
  
  
  CONCLUSIONS
  Our results show a potent anti-inflammatory and antinociceptive effect of P-317 in mouse models of colitis upon activation of opioid receptors. The unique bioavailability of P-317 after oral administration suggests that it is a promising drug candidate for future treatment of IBD.
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Łódź, Poland.
authors.forename: Marta
authors.initials: M
authors.lastname: Sobczak
authors.affiliation: Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Łódź, Poland.
authors.forename: Piotr K
authors.initials: PK
authors.lastname: Zakrzewski
authors.affiliation: Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Łódź, Poland.
authors.forename: Adam I
authors.initials: AI
authors.lastname: Cygankiewicz
authors.affiliation: Department of Digestive Tract Diseases, Faculty of Medicine, Medical University of Lodz, Łódź, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Mokrowiecka
authors.affiliation: Department of Gastroenterological Surgery, Tenth People's Hospital of Shanghai, School of Medicine, Tongji University, Shanghai, China.
authors.forename: Chunqiu
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Łódź, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Sałaga
authors.affiliation: Department of Digestive Tract Diseases, Faculty of Medicine, Medical University of Lodz, Łódź, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Małecka-Panas
authors.affiliation: Department of Pathology, Faculty of Medicine, Medical University of Lodz, Łódź, Poland.
authors.forename: Radzisław
authors.initials: R
authors.lastname: Kordek
authors.affiliation: Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Łódź, Poland.
authors.forename: Wanda M
authors.initials: WM
authors.lastname: Krajewska
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Łódź, Poland; Department of Gastroenterological Surgery, Tenth People's Hospital of Shanghai, School of Medicine, Tongji University, Shanghai, China. Electronic address: jakub.fichna@umed.lodz.pl.
authors.forename: Jakub
authors.initials: J
authors.lastname: Fichna
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000700:Analgesics / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D016022:Case-Control Studies; D003093:Colitis, Ulcerative / Q000188:drug therapy* / Q000503:physiopathology; D003424:Crohn Disease / Q000188:drug therapy* / Q000503:physiopathology; D016207:Cytokines / Q000378:metabolism; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D055815:Young Adult
chemical_list: C000597538:2',6'-dimethyltyrosyl-cyclo(lysyl-phenylalanyl-prolyl-aspartyl)amide; D000700:Analgesics; D000893:Anti-Inflammatory Agents; D016207:Cytokines; D010456:Peptides, Cyclic; D014409:Tumor Necrosis Factor-alpha; D014302:Trinitrobenzenesulfonic Acid; D016264:Dextran Sulfate
keywords: Abdominal pain; Cyclic opioid peptides; Endogenous opioid system; Inflammatory bowel diseases; Morphiceptin