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

• Published in: Journal of neurochemistry 2009-08, Vol.110 (4), p.1191-1202
• Main Authors: Sim-Selley, Laura J, Goforth, Paulette B, Mba, Mba U, Macdonald, Timothy L, Lynch, Kevin R, Milstien, Sheldon, Spiegel, Sarah, Satin, Leslie S, Welch, Sandra P, Selley, Dana E
• Format: Article
• Language: English
• Subjects: analgesia; Animals; Animals, Newborn; autoradiography; Binding, Competitive - physiology; Biochemistry; Biological and medical sciences; Cannabinoids - pharmacology; Cell receptors; Cell structures and functions; Cells, Cultured; Central nervous system; Central neurotransmission. Neuromudulation. Pathways and receptors; Cerebral Cortex - cytology; Cerebral Cortex - drug effects; Cerebral Cortex - metabolism; Coculture Techniques; Fundamental and applied biological sciences. Psychology; glutamate; GPCR; Guanosine 5'-O-(3-Thiotriphosphate) - metabolism; Hyperalgesia - drug therapy; Hyperalgesia - metabolism; Hyperalgesia - physiopathology; hypothermia; Lysophospholipids - metabolism; Molecular and cellular biology; Monoamines receptors (catecholamine, serotonine, histamine, acetylcholine); Neurology; Neurons; Neurons - cytology; Neurons - drug effects; Neurons - metabolism; Neurotransmitters; Oxadiazoles - pharmacology; Patch-Clamp Techniques; Proteins; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled - drug effects; Receptors, G-Protein-Coupled - metabolism; Receptors, Lysosphingolipid - agonists; Receptors, Lysosphingolipid - antagonists & inhibitors; Receptors, Lysosphingolipid - metabolism; Receptors, Neurotransmitter - drug effects; Receptors, Neurotransmitter - metabolism; Signal Transduction - drug effects; Signal Transduction - physiology; Sphingosine - analogs & derivatives; Sphingosine - metabolism; sphingosine-1-phosphate receptor; Sulfur Radioisotopes - metabolism; Synaptic Transmission - drug effects; Synaptic Transmission - physiology; Thiophenes - pharmacology; Vertebrates: nervous system and sense organs
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2009.06202.x

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 S1P₁ receptors. S1P receptor activation inhibited glutamatergic neurotransmission as determined by electrophysiological recordings in cortical neurons in vitro, and this effect was mimicked by SEW2871 and inhibited by VPC44116. Moreover, central administration of S1P produced in vivo effects resembling the actions of cannabinoids, including thermal antinociception, hypothermia, catalepsy and hypolocomotion, but these actions were independent of CB₁ receptors. At least one of the central effects of S1P, thermal antinociception, is also at least partly S1P₁ receptor 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 S1P₁ receptor contributes to S1P-mediated antinociception.