Abstract The nociceptin receptor (NOP) and its ligand (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 1.2 mg/kg produced a profound response within 5 hours. In BALB/c mice, LPS 4 mg/kg produced no response whereas 7 mg/kg resulted in a profound response within 24 hours. In Wistar rats 15 mg/kg LPS caused no septic response in 6/10 animals whereas 25 mg/kg resulted in marked lethargy before 24 hours. Splenic interleukin-1β mRNA in BALB/c mice, and serum TNF-α concentrations in Wistar rats increased after LPS injection in a dosedependent 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 24 hours. We conclude that LPS-inoculation in rodents is an unsuitable model for studying possible changes in the NOP-N/OFQ system in sepsis. Highlights • We assessed the responses to different doses of lipopolysaccharide (LPS) in C57BL/6 mice, BALB/c mice and Wistar rats. • No symptoms of illness were observed at 24 hours with lower doses of LPS • Higher doses of LPS produced pronounced lethargy before 24 hours. • LPS administration had no effect on the gene expression of the nociceptin/orphanin FQ (N/OFQ) receptor NOP and the N/OFQ receptor precursor ppN/OFQ. • This model is not suitable to study the effects of nociceptin on septic responses 3 Introduction The nociceptin system comprises the nociceptin receptor (NOP) and its 17 amino acid peptide ligand N/OFQ, which is cleaved from a precursor protein pre-pro nociceptin (ppN/OFQ
