The
ceramide-
sphingosine 1-phosphate (S1P) rheostat is important in regulating cell fate. Several chemotherapeutic agents, including
paclitaxel (
Taxol), involve pro-apoptotic
ceramide in their anticancer effects. The ceramide-to-S1P pathway is also implicated in the development of
pain, raising the intriguing possibility that these
sphingolipids may contribute to
chemotherapy- induced painful
peripheral neuropathy, which can be a critical dose-limiting side effect of many widely used chemotherapeutic agents.We demonstrate that the development of
paclitaxel-induced
neuropathic pain was associated with
ceramide and S1P formation in the spinal dorsal horn that corresponded with the engagement of
S1P receptor subtype 1 (S1PR(1))- dependent neuroinflammatory processes as follows: activation of redox-sensitive
transcription factors (NFκB) and MAPKs (ERK and p38) as well as enhanced formation of pro-inflammatory and neuroexcitatory
cytokines (TNF-α and IL-1β). Intrathecal delivery of the S1PR1 antagonist W146 reduced these neuroinflammatory processes but increased
IL-10 and
IL-4, potent anti-inflammatory/ neuroprotective
cytokines. Additionally, spinal W146 reversed established
neuropathic pain. Noteworthy, systemic administration of the S1PR1 modulator
FTY720 (Food and Drug Administration- approved for
multiple sclerosis) attenuated the activation of these neuroinflammatory processes and abrogated
neuropathic pain without altering anticancer properties of
paclitaxel and with beneficial effects extended to
oxaliplatin. Similar effects were observed with other structurally and chemically unrelated S1PR1 modulators (
ponesimod and CYM-5442) and S1PR1 antagonists (NIBR-14/15) but not S1PR1 agonists (
SEW2871). Our findings identify for the first time the S1P/S1PR1 axis as a promising molecular and therapeutic target in
chemotherapy-induced painful
peripheral neuropathy, establish a mechanistic insight into the biomolecular signaling pathways, and provide the rationale for the clinical evaluation of
FTY720 in
chronic pain patients.