Sphingosine 1-phosphate modulates spinal nociceptive processing.

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.

• Authors: Ovidiu Coste, Christian Brenneis, Bona Linke, Sandra Pierre, Christian Maeurer, Wiebke Becker, Helmut Schmidt, Wei Gao, Gerd Geisslinger, Klaus Scholich
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 283 Issue 47 Pg. 32442-51 (Nov 21 2008) ISSN: 0021-9258 [Print] United States
• PMID: 18805787 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Lysophospholipids
• dihydrosphingosine 1-phosphate
• sphingosine 1-phosphate
• Cyclic AMP
• Phosphotransferases (Alcohol Group Acceptor)
• sphingosine kinase
• Sphingosine

Topics

• Animals
• Behavior, Animal
• Cyclic AMP (metabolism)
• Fluorescence Resonance Energy Transfer
• Lysophospholipids (metabolism, physiology)
• Mice
• Mice, Knockout
• Neurons (metabolism)
• Pain (etiology, pathology)
• Phosphotransferases (Alcohol Group Acceptor) (genetics, physiology)
• Rats
• Rats, Sprague-Dawley
• Signal Transduction
• Sphingosine (analogs & derivatives, metabolism, physiology)
• Spine (pathology)