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.