Sphingosine‐1‐phosphate receptors mediate neuromodulatory functions in the CNS

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Abstract
Sphingosine‐1‐phosphate (S1P) is a ubiquitous, lipophilic cellular mediator that acts in part by activation of G‐protein‐coupled receptor. Modulation of S1P signaling is an emerging pharmacotherapeutic target for immunomodulatory drugs. Although multiple S1P receptor types exist in the CNS, little is known about their function. Here, we report that S1P stimulated G‐protein activity in the CNS, and results from [35S]GTPγS autoradiography using the S1P1‐selective agonist SEW2871 and the S1P1/3‐selective antagonist VPC44116 show that in several regions a majority of this activity is mediated by S1P1receptors. S1P receptor activation inhibited glutamatergic neurotransmission as determined by electrophysiological recordings in cortical neuronsin vitro, and this effect was mimicked by SEW2871 and inhibited by VPC44116. Moreover, central administration of S1P producedin vivoeffects resembling the actions of cannabinoids, including thermal antinociception, hypothermia, catalepsy and hypolocomotion, but these actions were independent of CB1receptors. At least one of the central effects of S1P, thermal antinociception, is also at least partly S1P1receptor mediated because it was produced by SEW2871 and attenuated by VPC44116. These results indicate that CNS S1P receptors are part of a physiologically relevant and widespread neuromodulatory system, and that the S1P1receptor contributes to S1P‐mediated antinociception.

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