Sphingosine-1-phosphate receptor 1 activation in astrocytes contributes to neuropathic pain.

TitleSphingosine-1-phosphate receptor 1 activation in astrocytes contributes to neuropathic pain.
Publication TypeJournal Article
Year of Publication2019
AuthorsChen Z, Doyle TM, Luongo L, Largent-Milnes TM, Giancotti LAntonio, Kolar G, Squillace S, Boccella S, Walker JK, Pendleton A, Spiegel S, Neumann WL, Vanderah TW, Salvemini D
JournalProc Natl Acad Sci U S A
Date Published2019 05 21
KeywordsAnimals, Astrocytes, Drug Evaluation, Preclinical, Female, Interleukin-10, Male, Mice, Neuralgia, Rats, Sprague-Dawley, Sphingosine-1-Phosphate Receptors, Sulfones, Triazoles

Neuropathic pain afflicts millions of individuals and represents a major health problem for which there is limited effective and safe therapy. Emerging literature links altered sphingolipid metabolism to nociceptive processing. However, the neuropharmacology of sphingolipid signaling in the central nervous system in the context of chronic pain remains largely unexplored and controversial. We now provide evidence that sphingosine-1-phosphate (S1P) generated in the dorsal horn of the spinal cord in response to nerve injury drives neuropathic pain by selectively activating the S1P receptor subtype 1 (S1PR1) in astrocytes. Accordingly, genetic and pharmacological inhibition of S1PR1 with multiple antagonists in distinct chemical classes, but not agonists, attenuated and even reversed neuropathic pain in rodents of both sexes and in two models of traumatic nerve injury. These S1PR1 antagonists retained their ability to inhibit neuropathic pain during sustained drug administration, and their effects were independent of endogenous opioid circuits. Moreover, mice with astrocyte-specific knockout of did not develop neuropathic pain following nerve injury, thereby identifying astrocytes as the primary cellular substrate of S1PR1 activity. On a molecular level, the beneficial reductions in neuropathic pain resulting from S1PR1 inhibition were driven by interleukin 10 (IL-10), a potent neuroprotective and anti-inflammatory cytokine. Collectively, our results provide fundamental neurobiological insights that identify the cellular and molecular mechanisms engaged by the S1PR1 axis in neuropathic pain and establish S1PR1 as a target for therapeutic intervention with S1PR1 antagonists as a class of nonnarcotic analgesics.

Alternate JournalProc Natl Acad Sci U S A
PubMed ID31068460
PubMed Central IDPMC6534990
Grant ListR01 GM043880 / GM / NIGMS NIH HHS / United States
U01 AI025903 / AI / NIAID NIH HHS / United States
UL1 TR002345 / TR / NCATS NIH HHS / United States
Faculty Member Reference: 
Tally Largent-Milnes, PhD
Todd Vanderah, PhD