title: Inhibition of constitutive nitric oxide production increases the severity of lipopolysaccharide-induced sickness behaviour: a role for TNF-alpha.
abstract: Administration of bacterial lipopolysaccharide (LPS) to rodents induces hypophagia, body weight loss and hypolocomotion, a constellation of symptoms collectively referred to as 'sickness behaviour'. We examined the role of the gaseous transmitter nitric oxide (NO) in mediating LPS-induced sickness behaviour in rats. Treatment with the non-selective NO synthase (NOS) inhibitor N(G)-nitro-L-arginine (L-NA) (20 mg/kg; i.p.) increased the severity of LPS-induced sickness behaviour in rats, suggesting that endogenous NO does not act as a mediator of LPS-induced sickness behaviour, but may rather have a protective role, acting in an inhibitory feedback manner to limit LPS-induced sickness. To evaluate the role of the different NOS isoforms in this response, we examined the effect of the neuronal NOS inhibitor, 7-nitroindazole (7-NI; 25 and 50 mg/kg; i.p.), and the inducible NOS inhibitor, aminoguanidine (AGN; 50 and 100 mg/kg; i.p.). Neither 7-NI nor AGN significantly altered LPS-induced sickness behaviour. Therefore, it is likely that the endothelial isoform of NOS mediates the effect of L-NA on LPS-induced sickness behaviour. As pro-inflammatory cytokines are mediators of LPS-induced sickness behaviour, we examined the effect of L-NA (20 mg/kg; i.p.) on LPS-induced interleukin (IL)-1beta, IL-6 and tumour necrosis factor (TNF)-alpha production. L-NA increased LPS-induced TNF-alpha without significantly altering IL-1beta or IL-6 production. Moreover, pre-treatment with the TNF-alpha inhibitor pentoxyfilline (25 mg/kg; i.p.) largely reversed the augmenting effect of L-NA on LPS-induced sickness behaviour, suggesting that the ability of L-NA to increase TNF-alpha production underpinned its ability to increase the severity of sickness. In conclusion, L-NA increases the severity of LPS-induced sickness behaviour, most likely by blocking the tonic inhibitory action of constitutively produced NO on TNF-alpha production.
authors.affiliation: Department of Pharmacology, National University of Ireland, Galway, Ireland. connort@tcd.ie
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Connor
authors.forename: Joan
authors.initials: J
authors.lastname: O'Sullivan
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Nolan
authors.forename: John P
authors.initials: JP
authors.lastname: Kelly
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D025461:Feedback, Physiological / Q000276:immunology; D007375:Interleukin-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000009:adverse effects*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D019335:Nitroarginine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012803:Sick Role; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D019335:Nitroarginine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase