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J. Biol. Chem., Vol. 283, Issue 47, 32442-32451, November 21, 2008

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Sphingosine 1-Phosphate Modulates Spinal Nociceptive Processing^*

From the Pharmazentrum Frankfurt, ZAFES, Institute for Clinical Pharmacology, Klinikum der Johann Wolfgang Goethe-Universität Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany

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.

Received for publication, August 19, 2008 , and in revised form, September 19, 2008.

^* This work was supported in part by DFG (German Research Association) Grants SCHO817-1 and SCHO817-2, the LOEWE Lipid Signaling Forschungszentrum Frankfurt (LIFF), and in part by an unrestricted grant from Aventis, Frankfurt, Germany. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ To whom correspondence should be addressed. Tel.: 49-0-69-6301-83103; Fax: 49-0-69-6301-83378; E-mail: scholich{at}em.uni-frankfurt.de.

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