Abstract
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 S1pr1 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.
Recommended Citation
Z. Chen and T. M. Doyle and L. Luongo and T. M. Largent-Milnes and L. A. Giancotti and G. Kolar and S. Squillace and S. Boccella and J. K. Walker and A. Pendleton and S. Spiegel and W. L. Neumann and T. W. Vanderah and D. Salvemini, "Sphingosine-1-phosphate Receptor 1 Activation In Astrocytes Contributes To Neuropathic Pain," Proceedings of the National Academy of Sciences of the United States of America, vol. 116, no. 21, pp. 10557 - 10562, National Academy of Sciences, Jan 2019.
The definitive version is available at https://doi.org/10.1073/pnas.1820466116
Department(s)
Biological Sciences
Publication Status
Free Access
Keywords and Phrases
Astrocytes; Interleukin 10; S1P receptor subtype 1; Sphingosine-1-phosphate; Traumatic nerve injury-induced neuropathic pain
International Standard Serial Number (ISSN)
1091-6490; 0027-8424
Document Type
Article - Journal
Document Version
Final Version
File Type
text
Language(s)
English
Rights
© 2025 The Authors, All rights reserved.
Creative Commons Licensing
This work is licensed under a Creative Commons Attribution 4.0 License.
Publication Date
01 Jan 2019
PubMed ID
31068460
Comments
National Institute of General Medical Sciences, Grant R01GM043880