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

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.

Targeting the Sphingosine-1-Phosphate Axis for Developing Non-narcotic Pain Therapeutics

“…These effects are abrogated in mice lacking the S1PR1 receptor on astrocytes, implying that the NLRP3 pathway is activated downstream of S1PR1 ( Figure 4A). The role of astrocyte-mediated S1PR1 neuroinflammation has also been documented in models of traumatic nerve injury [84]. Peripheral nerve damage induces increased S1P production and S1PR1 expression in the DHSC, leading to central sensitization triggered by NLRP3 inflammasome-derived IL-1β.…”

Genomewide Meta‐Analysis Validates a Role for S1PR1 in Microtubule Targeting Agent‐Induced Sensory Peripheral Neuropathy

“…28 In peripheral neurons, the S1P-to-S1PR 1 axis has been associated with increased neuronal excitability, 29 reduction in neuronal growth through Rho GTPase signaling, 30 and increased hyperalgesia, 31 and other pain-like behaviors. 32,33 The SNP with the strongest association with MTA-induced PN (rs74497159) is located in a genomic region experimentally defined as an enhancer with evidence for direct chromatin interactions with S1PR1 and numerous expression quantitative trait loci for S1PR1. Collectively, these bioinformatic data provide strong evidence that the identified genomic enhancer regions can regulate S1PR1 expression, although additional studies will be needed to extend these data to regulation of S1PR1 expression in peripheral SNs.…”

The ceramide-S1P pathway as a druggable target to alleviate peripheral neuropathic pain

“…Selective activation of S1P1 in astrocytes mediates neuropathic pain in a model of traumatic nerve injury and is attenuated by S1P1 antagonists and abolished in astrocyte-specific S1P1 knock-out mice. The inhibition of S1P1 and the reduction of neuropathic pain coincide with increased interleukin-10 (IL-10) levels, a potent neuroprotective and anti-inflammatory cytokine [115]. S1P3 is upregulated in astrocytes in response to simulated inflammation.…”

“…Several chemotherapeutic agents involve proapoptotic ceramide in their anticancer effects raising the intriguing possibility that sphingolipids may contribute to CIPN. S1P1 activation in astrocytes contributes to neuropathic pain [115]. The development of paclitaxel-induced neuropathic pain is associated with ceramide and S1P formation in the spinal dorsal horn and intrathecal delivery of S1P1 antagonists.…”