Sphingosine-1-phosphate acting via the S1P1 receptor is a downstream signaling pathway in ceramide-induced hyperalgesia

NEUROSCIENCE LETTERS

卷:499

Article

Doyle, Tim¹  Chen, Zhoumou¹  Obeid, Lina M.^2,3  Salvemini, Daniela¹ 

[1] St Louis Univ, Sch Med, Dept Pharmacol & Physiol Sci, St Louis, MO 63104 USA

[2] Med Univ S Carolina, Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC 29425 USA

[3] Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA

关键词: Ceramide;    Sphingosine-1-phosphate;    Sphingosine kinase;    Hyperalgesia;    Sphingosine-1-phosphate receptor subtype 1 (S1PR(1));   

DOI  :  10.1016/j.neulet.2011.05.018

来源: Elsevier

【 摘 要 】

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 (SIP), 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-a (TNF-alpha) in paw tissues. The development of hyperalgesia was significantly attenuated by a soluble TNF receptor I. TNF-alpha is known to activate SphK1, thus SIP production, and our results demonstrate that, 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-SI P antibody (LT1002). LT1017, the isotype-matched control monoclonal antibody for LT1002, had no effect. Our results further demonstrate that SIP contributes to the development of hyperalgesia via the SIP receptor 1 subtype (S1PR(1)), since responses were blocked by a well characterized S1PR(1) antagonist, W146, but not by its inactive enantiomer, W140. Collectively, these results provide mechanistic evidence implicating the S1P-to-S1PR(1) pathway as a downstream signaling pathway in ceramide-induced hyperalgesia. Targeting SIP may be a novel therapeutic approach in pain management. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

【 授权许可】

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