Sphingosine-1-phosphate acting via the S1P₁ receptor is a downstream signaling pathway in ceramide-induced hyperalgesia.
Sphingosine-1-phosphate acting via the S1P₁ receptor is a downstream signaling pathway in ceramide-induced hyperalgesia.
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DOI：
10.1016/j.neulet.2011.05.018
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发表时间：
2011-07-15
影响因子：
2.5
通讯作者：
Salvemini D
中科院分区：
文献类型：
--
作者：
Doyle T;Chen Z;Obeid LM;Salvemini D
神经酰胺是一种强有力的促炎鞘磷脂，最近被证明在大鼠身上产生了强烈的痛觉过敏反应。神经酰胺一旦产生，就会被鞘氨醇激酶(SphK)1和/或2转化为其活性代谢物之一-1-磷酸鞘氨醇(S1P)，进而通过G蛋白偶联的S1P受体传递信号。本论文的目的是明确神经酰胺引起的痛敏是否由S1P驱动。我们的结果表明，足底注射神经酰胺可导致大鼠热痛敏的时间依赖性发展，这与足爪组织中肿瘤坏死因子-α(Tumor-NectorFor-α)的增加有关。可溶性肿瘤坏死因子受体I可显著减轻痛觉过敏的发展。众所周知，肿瘤坏死因子-α能激活SphK1，从而产生S1P。为此，SphK1和SphK2的抑制剂(SK-I)和鼠抗S1P的单抗(LT1002)以剂量依赖的方式减弱了痛敏的发展。LT1002的同型相合对照单抗LT1017不起作用。我们的结果进一步证明，S1P通过S1P受体1亚型(S1PR1)参与痛觉过敏的发展，因为S1PR1拮抗剂W146可以阻断反应，但不能被它的非活性对映体W140阻断。总之，这些结果提供了机制证据，暗示S1P-to-S1PR1通路在神经酰胺诱导的痛觉过敏中是一条下游信号通路。靶向S1P可能是疼痛治疗的一种新的治疗方法。
Ceramide is a potent pro-inflammatory sphingolipid recently shown to exert potent hyperalgesic responses in rats. Once generated, ceramide is converted by sphingosine kinase (SphK) 1 and/or 2 to one of its active metabolite sphingosine-1-phosphate (S1P), which, in turn, signals through G-protein coupled S1P receptors. The objectives of this paper were to define whether ceramide-induced hyperalgesia is driven by S1P. Our results show that intraplantar injection of ceramide in rats led to a time-dependent development of thermal hyperalgesia that was associated with an increase in tumor necrosis factor-α (TNF-α) in paw tissues. The development of hyperalgesia was significantly attenuated by a soluble TNF receptor I. TNF-α is known to activate SphK1 and thus S1P production. To this end, the development of hyperalgesia was attenuated in a dose-dependent fashion by a well characterized inhibitor of SphK1 and SphK2 (SK-I) and by a murine monoclonal anti-S1P antibody (LT1002). LT1017, the isotype-matched control monoclonal antibody for LT1002, had no effect. Our results further demonstrate that S1P contributes to the development of hyperalgesia via the S1P receptor 1 subtype (S1PR1), since responses were blocked by a well characterized S1PR1 antagonist, W146, but not by its inactive enantiomer, W140. Collectively, these results provide mechanistic evidence implicating the S1P-to-S1PR1 pathway as a downstream signaling pathway in ceramide-induced hyperalgesia. Targeting S1P may be a novel therapeutic approach in pain management.
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DOI：
10.1097/01.ta.0000149495.44582.76
发表时间：
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影响因子：
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影响因子：
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作者：
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DOI：
10.1016/j.bbapap.2007.07.013
发表时间：
2008-01-01
影响因子：
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