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Connor, TJ,O'Sullivan, J,Nolan, Y,Kelly, JP
2002
February
Neuroimmunomodulation
Inhibition of constitutive nitric oxide production increases the severity of lipopolysaccharide-induced sickness behaviour: A role for TNF-alpha
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nitric oxide endothelial nitric oxide synthase sickness behaviour cytokine lipopolysaccharide tumour necrosis factor-alpha TUMOR-NECROSIS-FACTOR RAT-BRAIN SYNTHASE INHIBITORS PARAVENTRICULAR NUCLEUS 7-NITRO INDAZOLE INTERLEUKIN-1 CYTOKINES ENDOTOXIN MICE INDOMETHACIN
10
367
378
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-a 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-a 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. Copyright (C) 2003 S. Karger AG, Basel.
DOI 10.1159/000071478
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