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

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

  • Proc Natl Acad Sci U S A. 2019 May 21;116(21):10557-10562. doi: 10.1073/pnas.1820466116.
Zhoumou Chen 1 Timothy M Doyle 1 Livio Luongo 2 Tally M Largent-Milnes 3 Luigino Antonio Giancotti 1 Grant Kolar 4 Silvia Squillace 1 5 Serena Boccella 2 John K Walker 1 6 Alexander Pendleton 3 Sarah Spiegel 7 William L Neumann 8 Todd W Vanderah 3 Daniela Salvemini 9
Affiliations

Affiliations

  • 1 Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, MO 63104.
  • 2 Department of Experimental Medicine, Division of Pharmacology, Università della Campania Luigi Vanvitelli, 81100 Naples, Italy.
  • 3 Department of Pharmacology, University of Arizona College of Medicine, Tucson, AZ 85724.
  • 4 Department of Pathology, Saint Louis University School of Medicine, St. Louis, MO 63104.
  • 5 Department of Physiology and Pharmacology Vittorio Erspamer, Sapienza University of Rome, 00185 Rome, Italy.
  • 6 Department of Chemistry, Saint Louis University, St. Louis, MO 63104.
  • 7 Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298.
  • 8 Department of Pharmaceutical Sciences, School of Pharmacy, Southern Illinois University at Edwardsville, Edwardsville, IL 62026.
  • 9 Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, MO 63104; daniela.salvemini@health.slu.edu.
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.

Keywords

S1P receptor subtype 1; astrocytes; interleukin 10; sphingosine-1-phosphate; traumatic nerve injury-induced neuropathic pain.

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