Department of Neurology, University of Würzburg, Josef-Schneider-Str 11, 97080 Würzburg, Germany.
Mol Pain. 2010 Mar 2;6:13. doi: 10.1186/1744-8069-6-13.
Although it has been largely demonstrated that nitric oxide synthase (NOS), a key enzyme for nitric oxide (NO) production, modulates inflammatory pain, the molecular mechanisms underlying these effects remain to be clarified. Here we asked whether cytokines, which have well-described roles in inflammatory pain, are downstream targets of NO in inflammatory pain and which of the isoforms of NOS are involved in this process.
Intraperitoneal (i.p.) pretreatment with 7-nitroindazole sodium salt (7-NINA, a selective neuronal NOS inhibitor), aminoguanidine hydrochloride (AG, a selective inducible NOS inhibitor), L-N(G)-nitroarginine methyl ester (L-NAME, a non-selective NOS inhibitor), but not L-N(5)-(1-iminoethyl)-ornithine (L-NIO, a selective endothelial NOS inhibitor), significantly attenuated thermal hyperalgesia induced by intraplantar (i.pl.) injection of complete Freund's adjuvant (CFA). Real-time reverse transcription-polymerase chain reaction (RT-PCR) revealed a significant increase of nNOS, iNOS, and eNOS gene expression, as well as tumor necrosis factor-alpha (TNF), interleukin-1 beta (IL-1beta), and interleukin-10 (IL-10) gene expression in plantar skin, following CFA. Pretreatment with the NOS inhibitors prevented the CFA-induced increase of the pro-inflammatory cytokines TNF and IL-1beta. The increase of the anti-inflammatory cytokine IL-10 was augmented in mice pretreated with 7-NINA or L-NAME, but reduced in mice receiving AG or L-NIO. NNOS-, iNOS- or eNOS-knockout (KO) mice had lower gene expression of TNF, IL-1beta, and IL-10 following CFA, overall corroborating the inhibitor data.
These findings lead us to propose that inhibition of NOS modulates inflammatory thermal hyperalgesia by regulating cytokine expression.
尽管一氧化氮合酶（NOS）作为一氧化氮（NO）产生的关键酶，已被广泛证明可以调节炎症性疼痛，但这些作用的分子机制仍有待阐明。在这里，我们想知道细胞因子是否是炎症性疼痛中 NO 的下游靶点，以及 NOS 的哪种同工酶参与了这一过程。
腹腔内（i.p.）预处理 7-硝基吲唑钠盐（7-NINA，一种选择性神经元 NOS 抑制剂）、盐酸氨基胍（AG，一种选择性诱导型 NOS 抑制剂）、L-N（G）-硝基精氨酸甲酯（L-NAME，一种非选择性 NOS 抑制剂），但不是 L-N（5）-（1-亚氨基乙基）-鸟氨酸（L-NIO，一种选择性内皮 NOS 抑制剂），显著减轻了完全弗氏佐剂（CFA）足底注射引起的热痛觉过敏。实时逆转录聚合酶链反应（RT-PCR）显示，CFA 后足底皮肤中 nNOS、iNOS 和 eNOS 基因表达以及肿瘤坏死因子-α（TNF）、白细胞介素-1β（IL-1β）和白细胞介素-10（IL-10）基因表达显著增加。NOS 抑制剂预处理可防止 CFA 诱导的促炎细胞因子 TNF 和 IL-1β增加。在接受 7-NINA 或 L-NAME 预处理的小鼠中，抗炎细胞因子 IL-10 的增加增强，但在接受 AG 或 L-NIO 预处理的小鼠中减少。NOS-NK、iNOS-NK 或 eNOS-KO（KO）小鼠在 CFA 后 TNF、IL-1β 和 IL-10 的基因表达降低，总体上与抑制剂数据一致。
这些发现使我们提出抑制 NOS 通过调节细胞因子表达来调节炎症性热痛觉过敏。
