Nociceptin/orphanin FQ inhibition with SB612111 ameliorates dextran sodium sulfate-induced colitis

• Published in: European journal of pharmacology 2012-05, Vol.683 (1-3), p.285-293
• Main Authors: Alt, Carsten, Lam, Jennifer S., Harrison, M. Travis, Kershaw, Kathleen M., Samuelsson, Steven, Toll, Lawrence, D'Andrea, Annalisa
• Format: Article
• Language: English
• Subjects: Animals; antagonists; Anti-Inflammatory Agents, Non-Steroidal - therapeutic use; chemokines; colitis; Colitis - immunology; Colitis - metabolism; Colitis - physiopathology; Colitis - prevention & control; colon; Colon - drug effects; Colon - immunology; Colon - metabolism; Colon - pathology; Crohn disease; Cycloheptanes - therapeutic use; Cytokines - genetics; Cytokines - metabolism; dextran; Dextran sodium sulfate-induced colitis; Dextran Sulfate; diarrhea; Diarrhea - etiology; Diarrhea - prevention & control; disease course; etiology; Female; Gastrointestinal Hemorrhage - etiology; Gastrointestinal Hemorrhage - prevention & control; gene expression; Gene Expression Regulation - drug effects; hemorrhage; histopathology; immunomodulators; inflammation; Inflammatory bowel disease; interferon-gamma; interleukin-1beta; interleukin-6; Intestinal Mucosa - drug effects; Intestinal Mucosa - immunology; Intestinal Mucosa - metabolism; Intestinal Mucosa - pathology; Mice; Mice, Inbred C57BL; Molecular Targeted Therapy; N/OFQ receptor; Narcotic Antagonists; Nociceptin; Nociceptin Receptor; Nociceptin/orphanin FQ; Opioid Peptides - antagonists & inhibitors; pathogenesis; Piperidines - therapeutic use; receptors; Receptors, Opioid; RNA, Messenger - metabolism; Signal Transduction - drug effects; sodium; tumor necrosis factor-alpha; weight loss; Weight Loss - drug effects
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2012.03.014

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. [Display omitted]