Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St Louis, Missouri, United States of America.
PLoS One. 2013;8(1):e55255. doi: 10.1371/journal.pone.0055255. Epub 2013 Jan 25.
Novel classes of pain-relieving molecules are needed to fill the void between non-steroidal anti-inflammatory agents and narcotics. We have recently shown that intraplantar administration of sphingosine 1-phosphate (S1P) in rats causes peripheral sensitization and hyperalgesia through the S1P(1) receptor subtype (S1PR(1)): the mechanism(s) involved are largely unknown and were thus explored in the present study. Intraplantar injection of carrageenan in rats led to a time-dependent development of thermal hyperalgesia that was associated with pronounced edema and infiltration of neutrophils in paw tissues. Inhibition of 1) S1P formation with SK-I, a sphingosine kinase inhibitor, 2) S1P bioavailability with the S1P blocking antibody Sphingomab, LT1002 (but not its negative control, LT1017) or 3) S1P actions through S1PR(1) with the selective S1PR(1) antagonist, W146 (but not its inactive enantiomer, W140) blocked thermal hyperalgesia and infiltration of neutrophils. Taken together, these findings identify S1P as an important contributor to inflammatory pain acting through S1PR(1) to elicit hyperalgesia in a neutrophil-dependant manner. In addition and in further support, we demonstrate that the development of thermal hyperalgesia following intraplantar injection of S1P or SEW2871 (an S1PR(1) agonist) was also associated with neutrophilic infiltration in paw tissues as these events were attenuated by fucoidan, an inhibitor of neutrophilic infiltration. Importantly, FTY720, an FDA-approved S1P receptor modulator known to block S1P-S1PR(1) signaling, attenuated carrageenan-induced thermal hyperalgesia and associated neutrophil infiltration. Targeting the S1P/S1PR(1) axis opens a therapeutic strategy for the development of novel non-narcotic anti-hyperalgesic agents.
需要新型的止痛分子来填补非甾体抗炎药和麻醉性镇痛药之间的空白。我们最近表明，在大鼠足底注射鞘氨醇 1-磷酸（S1P）会通过 S1P（1）受体亚型（S1PR（1））引起外周敏化和痛觉过敏：涉及的机制在很大程度上尚不清楚，因此在本研究中进行了探索。在大鼠中，角叉菜胶的足底注射导致热痛觉过敏的时间依赖性发展，其与爪组织中明显的水肿和嗜中性粒细胞浸润有关。以下方法抑制了 1）S1P 的形成，使用鞘氨醇激酶抑制剂 SK-I，2）S1P 的生物利用度，使用 S1P 阻断抗体 Sphingomab、LT1002（而非其阴性对照 LT1017），3）S1P 通过 S1PR（1）的作用，使用选择性 S1PR（1）拮抗剂 W146（而非其无活性对映体 W140），阻断了热痛觉过敏和嗜中性粒细胞浸润。总的来说，这些发现表明 S1P 是一种重要的促炎性疼痛贡献因子，通过 S1PR（1）以依赖于嗜中性粒细胞的方式引起痛觉过敏。此外，进一步支持这一发现的是，在足底注射 S1P 或 SEW2871（S1PR（1）激动剂）后，热痛觉过敏的发展也与爪组织中的嗜中性粒细胞浸润有关，这些事件被岩藻聚糖，一种嗜中性粒细胞浸润抑制剂所减弱。重要的是，FTY720 是一种 FDA 批准的 S1P 受体调节剂，已知可阻断 S1P-S1PR（1）信号，可减轻角叉菜胶引起的热痛觉过敏和相关的嗜中性粒细胞浸润。靶向 S1P/S1PR（1）轴为开发新型非麻醉性抗痛觉过敏药物提供了一种治疗策略。
