title: 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.affiliation: Department of Cardiovascular Sciences, Division of Anaesthesia, Critical Care and Pain Management, University of Leicester, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, Leicester LE1 5WW, United Kingdom. Electronic address: rct17@le.ac.uk.
authors.forename: Roisin C
authors.initials: RC
authors.lastname: Thomas
authors.affiliation: Department of Cardiovascular Sciences, Division of Anaesthesia, Critical Care and Pain Management, University of Leicester, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, Leicester LE1 5WW, United Kingdom. Electronic address: mfb11@student.le.ac.uk.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Bath
authors.affiliation: Department of Infection, Inflammation and Immunity, University of Leicester, Medical Sciences Building, University Road, Leicester LE1 9HN, United Kingdom. Electronic address: cms13@le.ac.uk.
authors.forename: Cordula M
authors.initials: CM
authors.lastname: Stover
authors.affiliation: Department of Cardiovascular Sciences, Division of Anaesthesia, Critical Care and Pain Management, University of Leicester, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, Leicester LE1 5WW, United Kingdom. Electronic address: dgl3@le.ac.uk.
authors.forename: David G
authors.initials: DG
authors.lastname: Lambert
authors.affiliation: Department of Cardiovascular Sciences, Division of Anaesthesia, Critical Care and Pain Management, University of Leicester, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, Leicester LE1 5WW, United Kingdom. Electronic address: jt23@le.ac.uk.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Thompson
mesh_terms: D000818:Animals; D003508:Cycloheptanes / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D053583:Interleukin-1beta / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity*; D051379:Mice; D008807:Mice, Inbred BALB C; D018847:Opioid Peptides / Q000378:metabolism* / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011957:Receptors, Opioid / Q000378:metabolism*; D018805:Sepsis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000094942:Nociceptin Receptor; D000097629:Nociceptin
chemical_list: D003508:Cycloheptanes; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D018847:Opioid Peptides; D010880:Piperidines; D011957:Receptors, Opioid; D014409:Tumor Necrosis Factor-alpha; D000094942:Nociceptin Receptor; D000097629:Nociceptin; C479838:(Nphe(1),Arg(14),Lys(15))N-OFQ NH(2); C587672:IL1B protein, mouse; C482404:cis-1-methyl-7-((4-(2,6-dichlorophenyl)piperidin-1-yl)methyl)-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol
keywords: Nociceptin; Nociceptin receptor; Nociceptin/Orphanin FQ; SB-612111; Sepsis; UFP-101