Zhang Dong Dong, Linke Bona, Suo Jing, Zivkovic Aleksandra, Schreiber Yannick, Ferreirós Nerea, Henke Marina, Geisslinger Gerd, Stark Holger, Scholich Klaus
Biol Chem. 2015 Jun;396(6-7):783-94. doi: 10.1515/hsz-2014-0276.
FTY720 (fingolimod) is, after its phosphorylation by sphingosine kinase (SPHK) 2, a potent, non-selective sphingosine-1-phosphate (S1P) receptor agonist. FTY720 has been shown to reduce the nociceptive behavior in the paclitaxel model for chemotherapy-induced neuropathic pain through downregulation of S1P receptor 1 (S1P1) in microglia of the spinal cord. Here, we investigated the mechanisms underlying the antinociceptive effects of FTY720 in a model for trauma-induced neuropathic pain. We found that intrathecal administration of phosphorylated FTY720 (FTY720-P) decreased trauma-induced pain behavior in mice, while intraplantar administered FTY720-P had no effect. FTY720-P, but not FTY720, reduced the nociceptive behavior in SPHK2-deficient mice, suggesting the involvement of S1P receptors. Fittingly, intrathecal administration of antagonists for S1P1 or S1P3, W146 and Cay10444 respectively, abolished the antinociceptive effects of systemically administered FTY720, demonstrating that activation of both receptors in the spinal cord is necessary to induce antinociceptive effects by FTY720. Accordingly, intrathecal administration of S1P1 receptor agonists was not sufficient to evoke an antinociceptive effect. Taken together, the data show that, in contrast to its effects on chemotherapy-induced neuropathy, FTY720 reduces trauma-induced neuropathic pain by simultaneous activation of spinal S1P1 and S1P3 receptor subtypes.
FTY720（芬戈莫德）在被鞘氨醇激酶（SPHK）2磷酸化后，是一种强效、非选择性的1-磷酸鞘氨醇（S1P）受体激动剂。FTY720已被证明可通过下调脊髓小胶质细胞中的S1P受体1（S1P1），减轻紫杉醇模型中化疗诱导的神经性疼痛的伤害感受行为。在此，我们研究了FTY720在创伤性神经性疼痛模型中产生抗伤害感受作用的潜在机制。我们发现，鞘内注射磷酸化的FTY720（FTY720-P）可降低小鼠创伤诱导的疼痛行为，而足底注射FTY720-P则无此效果。FTY720-P而非FTY720可减轻SPHK2缺陷小鼠的伤害感受行为，提示S1P受体参与其中。相应地，鞘内分别注射S1P1或S1P3拮抗剂W146和Cay10444，可消除全身给药的FTY720的抗伤害感受作用，表明脊髓中这两种受体的激活对于FTY720诱导抗伤害感受作用是必要的。因此，鞘内注射S1P1受体激动剂不足以引发抗伤害感受作用。综上所述，数据表明，与它对化疗诱导的神经病变的作用相反，FTY720通过同时激活脊髓S1P1和S1P3受体亚型来减轻创伤诱导的神经性疼痛。
