title: Activation of the endogenous nociceptin system by selective nociceptin receptor agonist SCH 221510 produces antitransit and antinociceptive effect: a novel strategy for treatment of diarrhea-predominant IBS.
abstract: BACKGROUND
  Diarrhea-predominant irritable bowel syndrome (IBS-D) is a functional gastrointestinal (GI) disorder, defined by the presence of loose stools and abdominal pain. In search for a novel anti-IBS-D therapy, here we investigated the nociceptin receptor (NOP)-dependent effects in the GI tract.
  
  
  METHODS
  A novel potent and selective NOP agonist SCH 221510 was used in the study. The effect of NOP activation on mouse intestinal motility was characterized in vitro and in vivo, in physiological conditions and in animal models of hypermotility and diarrhea. Well-established mouse models of visceral pain were used to characterize the antinociceptive effect of the NOP activation. To provide additional evidence that the endogenous nociceptin system is a relevant target for IBS, NOP expression and nociceptin levels were quantified in serum and colonic biopsies from IBS-D patients.
  
  
  RESULTS
  SCH 221510 produced a potent NOP-mediated inhibitory effect on mouse intestinal motility in vitro and in vivo in physiological conditions. The NOP agonist displayed an antidiarrheal and analgesic action after oral administration in animal models mimicking the symptoms of IBS-D. Studies on human samples revealed a strong decrease in endogenous nociceptin system expression in IBS-D patients compared with healthy controls.
  
  
  CONCLUSIONS
  Collectively, mouse and human data suggest that the endogenous nociceptin system is involved in IBS-D and may become a target for anti-IBS-D treatments using potent and selective synthetic NOP agonists.
authors.affiliation: Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada; Division of Gastroenterology, Department of Medicine, University of Calgary, Calgary, AB, Canada; Department of Biochemistry, Medical University of Lodz, Lodz, Poland.
authors.forename: J
authors.initials: J
authors.lastname: Fichna
authors.forename: M
authors.initials: M
authors.lastname: Sobczak
authors.forename: A
authors.initials: A
authors.lastname: Mokrowiecka
authors.forename: A I
authors.initials: AI
authors.lastname: Cygankiewicz
authors.forename: P K
authors.initials: PK
authors.lastname: Zakrzewski
authors.forename: N
authors.initials: N
authors.lastname: Cenac
authors.forename: M
authors.initials: M
authors.lastname: Sałaga
authors.forename: J-P
authors.initials: JP
authors.lastname: Timmermans
authors.forename: N
authors.initials: N
authors.lastname: Vergnolle
authors.forename: E
authors.initials: E
authors.lastname: Małecka-Panas
authors.forename: W M
authors.initials: WM
authors.lastname: Krajewska
authors.forename: M
authors.initials: M
authors.lastname: Storr
mesh_terms: D000818:Animals; D053961:Azabicyclo Compounds / Q000494:pharmacology*; D003967:Diarrhea / Q000209:etiology; D004195:Disease Models, Animal; D005769:Gastrointestinal Motility / Q000187:drug effects*; D006801:Humans; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects*; D043183:Irritable Bowel Syndrome / Q000378:metabolism*; D008297:Male; D051379:Mice; D018847:Opioid Peptides / Q000378:metabolism*; D010146:Pain / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D011957:Receptors, Opioid / Q000819:agonists; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000094942:Nociceptin Receptor; D000097629:Nociceptin
chemical_list: D053961:Azabicyclo Compounds; D018847:Opioid Peptides; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor; D000097629:Nociceptin; C530605:8-(bis(2-methylphenyl)methyl)-3-phenyl-8-azabicyclo(3.2.1)octan-3-ol
keywords: diarrhea-predominant irritable bowel syndrome; nociceptin; nociceptin receptor; visceral pain