title: Anti-inflammatory and antinociceptive action of an orally available nociceptin receptor agonist SCH 221510 in a mouse model of inflammatory bowel diseases.
abstract: The nociceptin receptors (NOPs) are expressed in the gastrointestinal (GI) tract on muscle cell membranes and neurons, as well as the immune cells that infiltrate the mucosa. The involvement of NOPs in the pathophysiology of GI inflammation has been suggested, but due to the lack of selective NOP agonists, it never fully elucidated. Our aim was to characterize the anti-inflammatory and antinociceptive effect of the NOP agonist, SCH 221510 [3-endo-8-[bis(2-methylphenyl)methyl]-3-phenyl-8-azabicyclo [3.2.1]octan-3-ol], as a potential therapeutic strategy in the treatment of inflammatory bowel diseases (IBD). The anti-inflammatory action of SCH 221510 was determined after intraperitoneal, oral, and intracolonic administration of SCH 221510 (0.1-3.0 mg/kg once or twice daily) in mice treated with 2,4,6-trinitrobenzenesulfonic acid (TNBS). Antinociceptive action of SCH 221510 was evaluated in the mouse model of mustard oil (MO)-induced abdominal pain. Relative NOP mRNA expression was assessed in patients with IBD using real-time reverse transcriptase-polymerase chain reaction. We found that the expression of NOP mRNA was significantly decreased in patients with IBD. The administration (0.1 and 1.0 mg/kg i.p. twice daily and 3 mg/kg p.o. twice daily) of SCH 221510 attenuated TNBS colitis in mice. This effect was blocked by a selective NOP antagonist [J-113397 [(±)-1-[(3R*,4R*)-1-(cyclooctylmethyl)-3-(hydroxymethyl)-4-piperidinyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one]]. The intracolonic injections of SCH 221510 did not improve colitis in mice. The antinociceptive effect of SCH 221510 was observed after oral administration of SCH 221510 in MO-induced pain tests in mice with acute colitis. In conclusion, our results show a potent anti-inflammatory and antinociceptive effect upon selective activation of NOP receptors and suggest that the NOP agonist SCH 221510 is a promising drug candidate for future treatment of IBD.
authors.affiliation: Department of Biomolecular Chemistry (M.So., M.Sa., J.F.), Department of Digestive Tract Diseases (A.M., E.M.-P.), and Department of Pathology (R.K.), Faculty of Medicine, Medical University of Lodz, Lodz, Poland; Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland (A.I.C., P.K.Z., W.M.K.); and Department of Medicine, Division of Gastroenterology, Ludwig Maximilians University of Munich, Munich, Germany (M.St.).
authors.forename: Marta
authors.initials: M
authors.lastname: Sobczak
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: Martin
authors.initials: M
authors.lastname: Storr
authors.forename: Radzisław
authors.initials: R
authors.lastname: Kordek
authors.forename: Ewa
authors.initials: E
authors.lastname: Małecka-Panas
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; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use; D053961:Azabicyclo Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D016022:Case-Control Studies; D003093:Colitis, Ulcerative / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D003106:Colon / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D009149:Mustard Plant; D010938:Plant Oils; D011957:Receptors, Opioid / Q000819:agonists* / Q000378:metabolism; D014302:Trinitrobenzenesulfonic Acid; D055815:Young Adult; D000094942:Nociceptin Receptor
chemical_list: C530605:8-(bis(2-methylphenyl)methyl)-3-phenyl-8-azabicyclo(3.2.1)octan-3-ol; D000894:Anti-Inflammatory Agents, Non-Steroidal; D053961:Azabicyclo Compounds; D010938:Plant Oils; D011957:Receptors, Opioid; D014302:Trinitrobenzenesulfonic Acid; C027793:mustard oil; D000094942:Nociceptin Receptor