title: Orally administered novel cyclic pentapeptide P-317 alleviates symptoms of diarrhoea-predominant irritable bowel syndrome.
abstract: OBJECTIVE
  The aim of our study was to characterize the effect of P-317, a novel cyclic derivative of morphiceptin, on gastrointestinal (GI) motility and abdominal pain in mouse models mimicking symptoms of diarrhoea-predominant irritable bowel syndrome (IBS-D).
  
  
  METHODS
  The effect of P-317 on mouse intestinal motility was characterized in vitro and in vivo in physiological and pathophysiological conditions. The antinociceptive action of P-317 was characterized in the mustard oil-induced abdominal pain model and the writhing test. Locomotor activity and grip-strength tests were used to evaluate the effect of P-317 in the central nervous system (CNS). To translate our study to clinical conditions, the semi-quantitative expression of μ-opioid receptors (MOP) and κ-opioid receptors (KOP) messenger RNA (mRNA) in human colonic samples from IBS-D patients was quantified.
  
  
  RESULTS
  In vitro, P-317 (10(-10) -10(-6) M) inhibited colonic and ileal smooth muscle contractions in a concentration-dependent, β-funaltrexamine and nor-binaltorphimine-reversible manner. In vivo, P-317 (0.1 mg/kg, i.p. and 1 mg/kg, p.o.) inhibited GI transit, displayed a potent antinociceptive action in abdominal pain tests and did not influence the CNS.
  
  
  CONCLUSIONS
  P-317 produced a potent analgesic and antidiarrhoeal action in the mouse GI tract after oral administration. Given lower expression of MOP and KOP mRNA in IBS-D patients, P-317 is a promising peptide-based drug candidate for IBS-D 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.forename: Chunqiu
authors.initials: C
authors.lastname: Chen
authors.forename: Anna
authors.initials: A
authors.lastname: Mokrowiecka
authors.forename: Adam I
authors.initials: AI
authors.lastname: Cygankiewicz
authors.forename: Piotr K
authors.initials: PK
authors.lastname: Zakrzewski
authors.forename: Maciej
authors.initials: M
authors.lastname: Sałaga
authors.forename: Ewa
authors.initials: E
authors.lastname: Małecka-Panas
authors.forename: Piotr
authors.initials: P
authors.lastname: Wlaź
authors.forename: Wanda M
authors.initials: WM
authors.lastname: Krajewska
authors.forename: Jakub
authors.initials: J
authors.lastname: Fichna
mesh_terms: D015746:Abdominal Pain / Q000139:chemically induced / Q000188:drug therapy*; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000930:Antidiarrheals / Q000494:pharmacology / Q000627:therapeutic use*; D016022:Case-Control Studies; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D003967:Diarrhea / Q000188:drug therapy* / Q000209:etiology; D004195:Disease Models, Animal; D004723:Endorphins / Q000494:pharmacology / Q000627:therapeutic use*; D005772:Gastrointestinal Transit / Q000187:drug effects*; D006801:Humans; D007082:Ileum / Q000187:drug effects; D043183:Irritable Bowel Syndrome / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009149:Mustard Plant; D010938:Plant Oils; D011957:Receptors, Opioid / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D000700:Analgesics; D000930:Antidiarrheals; D004723:Endorphins; D010938:Plant Oils; D011957:Receptors, Opioid; C028889:morphiceptin; C027793:mustard oil
keywords: abdominal pain; diarrhoea; irritable bowel syndrome; morphiceptin; oral administration