title: Nociceptin/orphanin FQ inhibition with SB612111 ameliorates dextran sodium sulfate-induced colitis.
abstract: Inflammatory bowel diseases, primarily Crohn's disease and ulcerative colitis, are chronic inflammatory disorders of the gastrointestinal tract with unknown etiology. The majority of current therapeutic agents focus on controlling proinflammatory molecules. The neuropeptide nociceptin/orphanin FQ (N/OFQ) has been described as a potential immunomodulator for inflammatory bowel diseases. In this study, we asked whether the small molecule N/OFQ antagonist (-)-cis-1-methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol (SB612111) would inhibit the development of dextran sodium sulfate-induced colitis in C57BL/6 mice. Inhibition of the N/OFQ receptor (NOP) by SB612111 significantly ameliorated the clinical disease course in these animals, as indicated by reduced fecal bleeding, improved recovery from diarrhea and weight loss, and a reduction in histopathological alterations. In addition, the inflammatory response in the colon was diminished, as demonstrated by reduced cytokine protein and messenger RNA expression for CXCL1/keratinocyte-derived chemokine, interferon-γ, interleukin-1β, interleukin-6, and tumor necrosis factor-α, some of which are known targets for the treatment of this devastating disease. Our results strongly support a role for the receptor-ligand pair NOP-N/OFQ in the pathogenesis of colitis. We conclude that inhibition of NOP receptors with small molecule inhibitors may constitute a novel, urgently needed approach for the treatment of inflammatory bowel diseases.
authors.affiliation: SRI International, Biosciences Division, 333 Ravenswood Avenue, Menlo Park, CA 94025-3493, USA. carsten.alt@sri.com
authors.forename: Carsten
authors.initials: C
authors.lastname: Alt
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Lam
authors.forename: M Travis
authors.initials: MT
authors.lastname: Harrison
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Kershaw
authors.forename: Steven
authors.initials: S
authors.lastname: Samuelsson
authors.forename: Lawrence
authors.initials: L
authors.lastname: Toll
authors.forename: Annalisa
authors.initials: A
authors.lastname: D'Andrea
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D003092:Colitis / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D003106:Colon / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D003508:Cycloheptanes / Q000627:therapeutic use*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D016264:Dextran Sulfate; D003967:Diarrhea / Q000209:etiology / Q000517:prevention & control; D005260:Female; D006471:Gastrointestinal Hemorrhage / Q000209:etiology / Q000517:prevention & control; D005786:Gene Expression Regulation / Q000187:drug effects; D007413:Intestinal Mucosa / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy; D009292:Narcotic Antagonists; D018847:Opioid Peptides / Q000037:antagonists & inhibitors*; D010880:Piperidines / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D011957:Receptors, Opioid; D015398:Signal Transduction / Q000187:drug effects*; D015431:Weight Loss / Q000187:drug effects; D000094942:Nociceptin Receptor; D000097629:Nociceptin
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D003508:Cycloheptanes; D016207:Cytokines; D016264:Dextran Sulfate; D009292:Narcotic Antagonists; D018847:Opioid Peptides; D010880:Piperidines; D012333:RNA, Messenger; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor; D000097629:Nociceptin; C482404:cis-1-methyl-7-((4-(2,6-dichlorophenyl)piperidin-1-yl)methyl)-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol; C000722287:Oprl1 protein, mouse