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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.
AuthorsCarsten Alt, Jennifer S Lam, M Travis Harrison, Kathleen M Kershaw, Steven Samuelsson, Lawrence Toll, Annalisa D'Andrea
JournalEuropean journal of pharmacology (Eur J Pharmacol) Vol. 683 Issue 1-3 Pg. 285-93 (May 15 2012) ISSN: 1879-0712 [Electronic] Netherlands
PMID22449384 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2012 Elsevier B.V. All rights reserved.
Chemical References
  • Anti-Inflammatory Agents, Non-Steroidal
  • Cycloheptanes
  • Cytokines
  • Narcotic Antagonists
  • Opioid Peptides
  • Piperidines
  • RNA, Messenger
  • Receptors, Opioid
  • cis-1-methyl-7-((4-(2,6-dichlorophenyl)piperidin-1-yl)methyl)-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol
  • nociceptin
  • nociceptin receptor
  • Dextran Sulfate
Topics
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal (therapeutic use)
  • Colitis (immunology, metabolism, physiopathology, prevention & control)
  • Colon (drug effects, immunology, metabolism, pathology)
  • Cycloheptanes (therapeutic use)
  • Cytokines (genetics, metabolism)
  • Dextran Sulfate
  • Diarrhea (etiology, prevention & control)
  • Female
  • Gastrointestinal Hemorrhage (etiology, prevention & control)
  • Gene Expression Regulation (drug effects)
  • Intestinal Mucosa (drug effects, immunology, metabolism, pathology)
  • Mice
  • Mice, Inbred C57BL
  • Molecular Targeted Therapy
  • Narcotic Antagonists
  • Opioid Peptides (antagonists & inhibitors)
  • Piperidines (therapeutic use)
  • RNA, Messenger (metabolism)
  • Receptors, Opioid
  • Signal Transduction (drug effects)
  • Weight Loss (drug effects)

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