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. Issue 11 (15th July 2014)

• Record Type: Journal Article
• Authors: Fichna, J.; Sobczak, M.; Mokrowiecka, A.; Cygankiewicz, A. I.; Zakrzewski, P. K.; Cenac, N.; Sałaga, M.; Timmermans, J.‐P.; Vergnolle, N.; Małecka‐Panas, E.; Krajewska, W. M.; Storr, M.
• Is Part Of: Neurogastroenterology & motility. Volume 26:Issue 11(2014:Nov.)
• Page Start: 1539
• Page End: 1550
• Publication Date: 2014-07-15
• Subjects: Gastrointestinal system -- Motility -- Periodicals; Gastrointestinal system -- Innervation -- Periodicals; 616.33
• DOI: 10.1111/nmo.12390
• Languages: English
• ISSNs: 1350-1925

Abstract

<abstract abstract-type="main" id="nmo12390-abs-0001"> <title>Abstract</title> <sec id="nmo12390-sec-0001" sec-type="section"> <title>Background</title> <p>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.</p> </sec> <sec id="nmo12390-sec-0002" sec-type="section"> <title>Methods</title> <p>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 <italic>in vitro</italic> and <italic>in vivo</italic>, 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.</p> </sec> <sec id="nmo12390-sec-0003" sec-type="section"> <title>Key Results</title> <p>SCH 221510 produced a potent NOP‐mediated inhibitory effect on mouse intestinal motility <italic>in vitro</italic> and <italic>in vivo</italic> 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.</p> </sec> <sec id="nmo12390-sec-0004" sec-type="section"> <title>Conclusions & Inferences</title> <p>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.</p> </sec> </abstract>