Sphingosine 1-phosphate mediates hyperalgesia via a neutrophil-dependent mechanism.
Sphingosine 1-phosphate mediates hyperalgesia via a neutrophil-dependent mechanism.
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DOI：
10.1371/journal.pone.0055255
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Salvemini D
中科院分区：
文献类型：
--
作者：
Finley A;Chen Z;Esposito E;Cuzzocrea S;Sabbadini R;Salvemini D
需要新型止痛分子来填补非甾体抗炎药和麻醉药之间的空白。我们最近发现，大鼠足底注射 1-磷酸鞘氨醇 (S1P) 可通过 S1P1 受体亚型 (S1PR1) 引起外周敏化和痛觉过敏：所涉及的机制很大程度上未知，因此在本研究中进行了探索。大鼠足底注射角叉菜胶会导致热痛觉过敏的时间依赖性发展，这与爪组织中明显的水肿和中性粒细胞浸润有关。 1) 使用鞘氨醇激酶抑制剂 SK-I 抑制 S1P 形成，2) 使用 S1P 阻断抗体 Sphingomab LT1002（但不是其阴性对照 LT1017）抑制 S1P 生物利用度，或 3) 使用选择性 S1PR1 拮抗剂 W146（但不是其无活性对映异构体 W140）通过 S1PR1 发挥 S1P 作用，阻断热痛觉过敏和中性粒细胞浸润。综上所述，这些发现表明 S1P 是炎症性疼痛的重要促成因素，通过 S1PR1 以中性粒细胞依赖性方式引起痛觉过敏。此外，在进一步的支持中，我们证明足底注射 S1P 或 SEW2871（一种 S1PR1 激动剂）后热痛觉过敏的发生也与爪组织中的中性粒细胞浸润有关，因为这些事件被中性粒细胞浸润抑制剂岩藻依聚糖减弱。重要的是，FTY720 是 FDA 批准的 S1P 受体调节剂，已知可阻断 S1P-S1PR1 信号传导，减轻角叉菜胶引起的热痛觉过敏和相关的中性粒细胞浸润。靶向 S1P/S1PR1 轴为开发新型非麻醉性抗痛觉过敏药物开辟了一种治疗策略。
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 S1P1 receptor subtype (S1PR1): 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 S1PR1 with the selective S1PR1 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 S1PR1 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 S1PR1 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-S1PR1 signaling, attenuated carrageenan-induced thermal hyperalgesia and associated neutrophil infiltration. Targeting the S1P/S1PR1 axis opens a therapeutic strategy for the development of novel non-narcotic anti-hyperalgesic agents.
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DOI：
10.1097/01.ta.0000149495.44582.76
发表时间：
2004-11-01
影响因子：
--
作者：
Lee, C;Xu, DZ;Hauser, CJ
通讯作者：
Hauser, CJ
影响因子：
7.4
作者：
Bennett, G;al-Rashed, S;Brain, SD
通讯作者：
Brain, SD
影响因子：
4.8
作者：
Brinkmann, V;Davis, MD;Lynch, KR
通讯作者：
Lynch, KR
影响因子：
4.8
作者：
Cuzzocrea, S;Misko, TP;Salvemini, D
通讯作者：
Salvemini, D
影响因子：
5.5
作者：
Cunha, Thiago M.;Verri, Waldiceu A., Jr.;Cunha, Fernando Q.
通讯作者：
Cunha, Fernando Q.