Sphingosine-1-phosphate receptors mediate neuromodulatory functions in the CNS.
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 [(35)S]GTPgammaS autoradiography using the S1P(1)-selective agonist SEW2871 and the S1P(1/3)-selective antagonist VPC44116 show that in several regions a majority of this activity is mediated by S1P(1) 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 CB(1) receptors. At least one of the central effects of S1P, thermal antinociception, is also at least partly S1P(1) 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 S1P(1) receptor contributes to S1P-mediated antinociception.
Sim-Selley
Laura J
LJ
Department of Pharmacology and Toxicology and Institute for Drug and Alcohol Studies, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298, USA. ljsimsel@vcu.edu
Goforth
Paulette B
PB
Mba
Mba U
MU
Macdonald
Timothy L
TL
Lynch
Kevin R
KR
Milstien
Sheldon
S
Spiegel
Sarah
S
Satin
Leslie S
LS
Welch
Sandra P
SP
Selley
Dana E
DE
D000818:Animals; D000831:Animals, Newborn; D001667:Binding, Competitive / Q000502:physiology; D002186:Cannabinoids / Q000494:pharmacology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018920:Coculture Techniques; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006930:Hyperalgesia / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D008246:Lysophospholipids / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010069:Oxadiazoles / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects / Q000378:metabolism*; D049349:Receptors, Lysosphingolipid / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017981:Receptors, Neurotransmitter / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D013462:Sulfur Radioisotopes / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D013876:Thiophenes / Q000494:pharmacology
D002186:Cannabinoids; D008246:Lysophospholipids; D010069:Oxadiazoles; D043562:Receptors, G-Protein-Coupled; D049349:Receptors, Lysosphingolipid; D017981:Receptors, Neurotransmitter; C503964:SEW2871; D013462:Sulfur Radioisotopes; D013876:Thiophenes; C060506:sphingosine 1-phosphate; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D013110:Sphingosine