Sphingosine 1-Phosphate Modulates Spinal Nociceptive Processing

Gerd Geisslinger,Wei Gao,Wiebke Becker,Christian Brenneis,Christian Maeurer,Klaus Scholich,Ovidiu Coste,Sandra Pierre,Helmut Schmidt,Bona Linke

doi:10.1074/jbc.m806410200

Gerd Geisslinger, Wei Gao + Show 8 more

Open Access

https://doi.org/10.1074/jbc.m806410200

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Abstract

Sphingosine 1-Phosphate (S1P) modulates various cellular functions such as apoptosis, cell differentiation, and migration. Although S1P is an abundant signaling molecule in the central nervous system, very little is known about its influence on neuronal functions. We found that S1P concentrations were selectively decreased in the cerebrospinal fluid of adult rats in an acute and an inflammatory pain model. Pharmacological inhibition of sphingosine kinases (SPHK) decreased basal pain thresholds and SphK2 knock-out mice, but not SphK1 knock-out mice, had a significant decrease in withdrawal latency. Intrathecal application of S1P or sphinganine 1-phosphate (dihydro-S1P) reduced the pain-related (nociceptive) behavior in the formalin assay. S1P and dihydro-S1P inhibited cyclic AMP (cAMP) synthesis, a key second messenger of spinal nociceptive processing, in spinal cord neurons. By combining fluorescence resonance energy transfer (FRET)-based cAMP measurements with Multi Epitope Ligand Cartography (MELC), we showed that S1P decreased cAMP synthesis in excitatory dorsal horn neurons. Accordingly, intrathecal application of dihydro-S1P abolished the cAMP-dependent phosphorylation of NMDA receptors in the outer laminae of the spinal cord. Taken together, the data show that S1P modulates spinal nociceptive processing through inhibition of neuronal cAMP synthesis.

Highlights

Lular functions such as apoptosis, cell differentiation, and migration either through the activation of a family of five G-protein-coupled receptors (S1P1–5) or by acting as an intracellular second messenger (1–3)
We show that peripheral nociceptive stimulation decreases Sphingosine 1-Phosphate (S1P) concentrations in the cerebrospinal fluid and that inhibition of spinal S1P synthesis lowers pain thresholds
Toward the mechanism of the antinociceptive actions of S1P, we found that S1P decreases the cyclic AMP (cAMP) synthesis in excitatory spinal cord neurons and prevents the cAMP-dependent phosphorylation of NMDA receptors in the outer laminae of the dorsal horn

Summary

Introduction

Lular functions such as apoptosis, cell differentiation, and migration either through the activation of a family of five G-protein-coupled receptors (S1P1–5) or by acting as an intracellular second messenger (1–3). Toward the mechanism of the antinociceptive actions of S1P, we found that S1P decreases the cAMP synthesis in excitatory spinal cord neurons and prevents the cAMP-dependent phosphorylation of NMDA receptors in the outer laminae of the dorsal horn.

Results

Conclusion