Nociceptin/Orphanin FQ system and animal models of sepsis

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 three different experimental animal models for studying changes in the nociceptin system; lipopolysaccharide (LPS)-induced sepsis, faecal slurry-induced sepsis and caecal ligation and puncture-induced sepsis. Methods. LPS-induced sepsis: C57BL/6mice 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). Fecal slurry-induced sepsis: A human stool batch was processed and a defined volume of stool suspension was injected intraperitoneally. Caecal ligation and puncture-induced sepsis: CLP was performed over 96 hours with and without the nociceptin receptor antagonist SB-612111. Results: In C57BL/6 mice LPS 0.85 mg/kg injection produced no septic response, whereas 1.2 mg/kg produced a profound response within 5 h. In BALB/c mice, LPS 4 mg/kg produced no response, whereas 7 mg/kg resulted in a profound response within 24 h. In Wistar rats LPS 15 mg/kg caused no septic response in 6/10 animals, whereas 25 mg/kg resulted in marked lethargy before 24 h. 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 24 h. Faecal slurry-induced sepsis produced a similar dose response curve to LPS and did not produce changes in the N/OFQ system within 24 h however, this model could not be fully evaluated due to licence restrictions preventing the addition of supportive therapy. In the caecal ligation and puncture studies some changes were observed in the N/OFQ system in brain tissues and in serum and in some cases appeared to be reversed by SB-612111. The relevance of these changes to sepsis is not clear. Conclusion: A) LPS-inoculation in rodents is an unsuitable model for studying possible changes in the NOP-N/OFQ system in sepsis B) the faecal slurry-induced sepsis model could possibly be suitable with modifications e.g. with the addition of supportive therapy but further work is needed to evaluate this. C) Caecal ligation and puncture is suitable for studying changes in the nociceptin system.