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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 EMAIL logo
Published/Copyright: January 23, 2015
Biological Chemistry
From the journal Biological Chemistry Volume 396 Issue 6-7

Abstract

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.

Keywords: FTY720; neuropathic pain; sphingosine-1-phosphate; S1P receptor; spinal cord
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:

Acknowledgments

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

©2015 by De Gruyter

Articles in the same Issue

  1. Frontmatter
  2. Guest Editorial
  3. Highlight: Molecular Medicine of Sphingolipids
  4. HIGHLIGHT: MOLECULAR MEDICINE OF SPHINGOLIPIDS
  5. The role of serum amyloid A and sphingosine-1-phosphate on high-density lipoprotein functionality
  6. Sphingolipids in viral infection
  7. Tackling the biophysical properties of sphingolipids to decipher their biological roles
  8. Ceramide and sphingosine in pulmonary infections
  9. Molecular mechanisms of erythrocyte aging
  10. Sphingolipids in liver injury, repair and regeneration
  11. Ultrasound-stimulated microbubble enhancement of radiation response
  12. Innate immune responses in the brain of sphingolipid lysosomal storage diseases
  13. Novel mechanisms of action of classical chemotherapeutic agents on sphingolipid pathways
  14. The role of sphingolipids in endothelial barrier function
  15. The effect of altered sphingolipid acyl chain length on various disease models
  16. Secretory sphingomyelinase in health and disease
  17. Preclinical development of a C6-ceramide NanoLiposome, a novel sphingolipid therapeutic
  18. Sphingomyelin breakdown in T cells: role in activation, effector functions and immunoregulation
  19. The molecular medicine of acid ceramidase
  20. Caenorhabditis elegans as a model to study sphingolipid signaling
  21. S1PR4 is required for plasmacytoid dendritic cell differentiation
  22. Antinociceptive effects of FTY720 during trauma-induced neuropathic pain are mediated by spinal S1P receptors
  23. Subcellular distribution of FTY720 and FTY720-phosphate in immune cells – another aspect of Fingolimod action relevant for therapeutic application
  24. Downregulation of sphingosine 1-phosphate (S1P) receptor 1 by dexamethasone inhibits S1P-induced mesangial cell migration
  25. Sphingosine kinase 2 deficiency increases proliferation and migration of renal mouse mesangial cells and fibroblasts
  26. Obituary
  27. The life and work of Dr. Robert Bittman (1942–2014)
https://doi.org/10.1515/hsz-2014-0276
Keywords for this article
FTY720; neuropathic pain; sphingosine-1-phosphate; S1P receptor; spinal cord

Articles in the same Issue

  1. Frontmatter
  2. Guest Editorial
  3. Highlight: Molecular Medicine of Sphingolipids
  4. HIGHLIGHT: MOLECULAR MEDICINE OF SPHINGOLIPIDS
  5. The role of serum amyloid A and sphingosine-1-phosphate on high-density lipoprotein functionality
  6. Sphingolipids in viral infection
  7. Tackling the biophysical properties of sphingolipids to decipher their biological roles
  8. Ceramide and sphingosine in pulmonary infections
  9. Molecular mechanisms of erythrocyte aging
  10. Sphingolipids in liver injury, repair and regeneration
  11. Ultrasound-stimulated microbubble enhancement of radiation response
  12. Innate immune responses in the brain of sphingolipid lysosomal storage diseases
  13. Novel mechanisms of action of classical chemotherapeutic agents on sphingolipid pathways
  14. The role of sphingolipids in endothelial barrier function
  15. The effect of altered sphingolipid acyl chain length on various disease models
  16. Secretory sphingomyelinase in health and disease
  17. Preclinical development of a C6-ceramide NanoLiposome, a novel sphingolipid therapeutic
  18. Sphingomyelin breakdown in T cells: role in activation, effector functions and immunoregulation
  19. The molecular medicine of acid ceramidase
  20. Caenorhabditis elegans as a model to study sphingolipid signaling
  21. S1PR4 is required for plasmacytoid dendritic cell differentiation
  22. Antinociceptive effects of FTY720 during trauma-induced neuropathic pain are mediated by spinal S1P receptors
  23. Subcellular distribution of FTY720 and FTY720-phosphate in immune cells – another aspect of Fingolimod action relevant for therapeutic application
  24. Downregulation of sphingosine 1-phosphate (S1P) receptor 1 by dexamethasone inhibits S1P-induced mesangial cell migration
  25. Sphingosine kinase 2 deficiency increases proliferation and migration of renal mouse mesangial cells and fibroblasts
  26. Obituary
  27. The life and work of Dr. Robert Bittman (1942–2014)
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