Accessible Unlicensed Requires Authentication Published by De Gruyter January 23, 2015

Antinociceptive effects of FTY720 during trauma-induced neuropathic pain are mediated by spinal S1P receptors

Dong Dong Zhang, Bona Linke, Jing Suo, Aleksandra Zivkovic, Yannick Schreiber, Nerea Ferreirós, Marina Henke, Gerd Geisslinger, Holger Stark and Klaus Scholich
From the journal Biological Chemistry


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.

Corresponding author: Klaus Scholich, Institut für Klinische Pharmakologie, pharmazentrum frankfurt/ZAF, E.S., Klinikum der Goethe-Universität Frankfurt, Theodor-Stern-Kai 7, D-60590 Frankfurt/Main, Germany, e-mail:


We would like to thank Namir Abazi for assistance with the label-free assay. This work was supported by the Deutsche Forschungsgemeinschaft (DFG) grants SCHO817–3, SFB1039 TPA08, INST 208/664–1. FU, and an unrestricted grant from Mundipharma Research GmbH & Co KG.


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Supplemental Material:

The online version of this article (DOI: 10.1515/hsz-2014-0276) offers supplementary material, available to authorized users.

Received: 2014-11-27
Accepted: 2015-1-16
Published Online: 2015-1-23
Published in Print: 2015-6-1

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