Connor Thomas J, O'Sullivan Joan, Nolan Yvonne, Kelly John P
Department of Pharmacology, National University of Ireland, Galway, Ireland.
Neuroimmunomodulation. 2002;10(6):367-78. doi: 10.1159/000071478.
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.
给啮齿动物注射细菌脂多糖（LPS）会引发摄食减少、体重减轻和运动减少，这一系列症状统称为“疾病行为”。我们研究了气体递质一氧化氮（NO）在介导LPS诱导的大鼠疾病行为中的作用。用非选择性一氧化氮合酶（NOS）抑制剂N（G）-硝基-L-精氨酸（L-NA）（20毫克/千克；腹腔注射）处理可增加LPS诱导的大鼠疾病行为的严重程度，这表明内源性NO并非LPS诱导的疾病行为的介质，而是可能具有保护作用，以抑制性反馈方式发挥作用来限制LPS诱导的疾病。为了评估不同NOS同工型在该反应中的作用，我们研究了神经元NOS抑制剂7-硝基吲唑（7-NI；25和50毫克/千克；腹腔注射）和诱导型NOS抑制剂氨基胍（AGN；50和100毫克/千克；腹腔注射）的作用。7-NI和AGN均未显著改变LPS诱导的疾病行为。因此，很可能是NOS的内皮同工型介导了L-NA对LPS诱导的疾病行为的影响。由于促炎细胞因子是LPS诱导的疾病行为的介质，我们研究了L-NA（20毫克/千克；腹腔注射）对LPS诱导的白细胞介素（IL）-1β、IL-6和肿瘤坏死因子（TNF）-α产生的影响。L-NA增加了LPS诱导的TNF-α产生，而未显著改变IL-1β或IL-6的产生。此外，用TNF-α抑制剂己酮可可碱（25毫克/千克；腹腔注射）预处理在很大程度上逆转了L-NA对LPS诱导的疾病行为的增强作用，这表明L-NA增加TNF-α产生的能力是其增加疾病严重程度的基础。总之，L-NA增加了LPS诱导的疾病行为的严重程度，很可能是通过阻断组成型产生的NO对TNF-α产生的持续性抑制作用。
