Exploring LPS-induced sepsis in rats and mice as a model to study potential protective effects of the nociceptin/orphanin FQ system.

Abstract

The nociceptin receptor (NOP) and its ligand nociceptin/orphanin FQ (N/OFQ) have been shown to exert a modulatory effect on immune cells during sepsis. We evaluated the suitability of an experimental lipopolysaccharide (LPS)-induced sepsis model for studying changes in the nociceptin system. C57BL/6 mice BALB/c mice and Wistar rats were inoculated with different doses of LPS with or without a nociceptin receptor antagonist (UFP-101 or SB-612111). In C57BL/6 mice LPS 0.85 mg/kg injection produced no septic response, whereas 1.2mg/kg produced a profound response within 5h. In BALB/c mice, LPS 4 mg/kg produced no response, whereas 7 mg/kg resulted in a profound response within 24h. In Wistar rats LPS 15 mg/kg caused no septic response in 6/10 animals, whereas 25mg/kg resulted in marked lethargy before 24h. Splenic interleukin-1β mRNA in BALB/c mice, and serum TNF-α concentrations in Wistar rats increased after LPS injection in a dose-dependent manner, but were undetectable in control animals, indicating that LPS had stimulated an inflammatory reaction. IL-1β and TNF-α concentrations in LPS-treated animals were unaffected by administration of a NOP antagonist. Similarly NOP antagonists had no effect on survival or expression of mRNA for NOP or ppN/OFQ (the N/OFQ precursor) in a variety of tissues. In these animal models, the dose-response curve for LPS was too steep to allow use in survival studies and no changes in the N/OFQ system occurred within 24h. We conclude that LPS-inoculation in rodents is an unsuitable model for studying possible changes in the NOP-N/OFQ system in sepsis.

• Authors: Roisin C Thomas, Michael F Bath, Cordula M Stover, David G Lambert, Jonathan P Thompson
• Journal: Peptides (Peptides) Vol. 61 Pg. 56-60 (Nov 2014) ISSN: 1873-5169 [Electronic] United States
• PMID: 25161013 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• (Nphe(1),Arg(14),Lys(15))N-OFQ NH(2)
• Cycloheptanes
• IL1B protein, mouse
• Interleukin-1beta
• Lipopolysaccharides
• Opioid Peptides
• Piperidines
• Receptors, Opioid
• Tumor Necrosis Factor-alpha
• cis-1-methyl-7-((4-(2,6-dichlorophenyl)piperidin-1-yl)methyl)-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol
• nociceptin
• Nociceptin Receptor

Topics

• Animals
• Cycloheptanes (pharmacology)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Interleukin-1beta (metabolism)
• Lipopolysaccharides (toxicity)
• Mice
• Mice, Inbred BALB C
• Opioid Peptides (metabolism, pharmacology)
• Piperidines (pharmacology)
• Rats
• Rats, Wistar
• Receptors, Opioid (metabolism)
• Sepsis (chemically induced, metabolism, pathology)
• Tumor Necrosis Factor-alpha (metabolism)
• Nociceptin Receptor