Pain Research Center, Department of Anesthesiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0531, USA.
Neurosci Lett. 2012 Apr 25;515(1):61-5. doi: 10.1016/j.neulet.2012.03.019. Epub 2012 Mar 16.
Sphingosine 1-phosphate (S1P) is a key immune mediator regulating migration of immune cells to sites of inflammation. S1P actions are mediated by a family of five G protein-coupled receptors. Sensory neurons express many of these receptors, and in vitro S1P has excitatory effects on small-diameter sensory neurons, many mediated by the S1P receptor 1 (S1PR1). This study investigated the role of S1P in regulating the sensitivity of DRG neurons. We found that in vivo perfusion of the normal L5 DRG with S1P increased mechanical sensitivity. Microelectrode recordings in isolated whole ganglia showed that large- and medium-diameter cells, as well as small-diameter cells, increased firing in the presence of S1P. To further determine the role of S1PRs, we examined the effects of in vivo S1PR1 knockdown in the L4 and L5 sensory ganglia. Small interfering RNA directed against S1PR1 did not affect baseline mechanical sensitivity in normal animals, in which S1P levels are expected to be low. However, when the L5 ganglion was locally inflamed, a procedure that leads to rapid and sustained mechanical hypersensitivity, S1PR1 siRNA injected animals showed significantly less hypersensitivity than animals injected with scrambled siRNA. Reduced expression of S1PR1, but not S1PR2 or S1PR3, was confirmed with qPCR methods. The results indicate that the S1PR1 receptors in sensory ganglia cells may play an important role in regulating behavioral sensitivity during inflammation.
鞘氨醇 1-磷酸（S1P）是一种关键的免疫介质，可调节免疫细胞向炎症部位迁移。S1P 通过一系列五种 G 蛋白偶联受体发挥作用。感觉神经元表达其中许多受体，体外 S1P 对小直径感觉神经元具有兴奋作用，许多作用是通过 S1P 受体 1（S1PR1）介导的。本研究探讨了 S1P 在调节 DRG 神经元敏感性中的作用。我们发现，在体灌流正常 L5 DRG 的 S1P 可增加机械敏感性。在分离的全神经节中的微电极记录显示，大直径和中直径细胞以及小直径细胞在存在 S1P 的情况下增加放电。为了进一步确定 S1PR 的作用，我们检查了体内 S1PR1 敲低在 L4 和 L5 感觉神经节中的作用。针对 S1PR1 的小干扰 RNA 不会影响正常动物的基线机械敏感性，在正常动物中 S1P 水平预计较低。然而，当 L5 神经节局部发炎时，一种导致快速和持续机械性超敏反应的程序，与注射 scrambled siRNA 的动物相比，注射 S1PR1 siRNA 的动物表现出的超敏反应明显减轻。用 qPCR 方法证实了 S1PR1 的表达减少，但 S1PR2 或 S1PR3 的表达没有减少。结果表明，感觉神经节细胞中的 S1PR1 受体可能在炎症期间调节行为敏感性方面发挥重要作用。
