Decision Letter: The Signaling Lipid Sphingosine 1-Phosphate Regulates Mechanical Pain

The study demonstrated that sphingosine 1-phosphate (S1P) and its receptor S1P Receptor 3 (S1PR3) played a crucial role in regulating acute mechanical pain. Disruption of S1PR3 or blocking S1P production significantly reduced responses to painful mechanical stimuli, mediated by A mechanonociceptors with decreased mechanosensitivity in S1PR3 mutant mice. S1PR3 signaling modulated mechanonociceptor excitability through KCNQ2/3 channels, highlighting the importance of S1P/S1PR3 in mechanical pain thresholds. Additionally, 43% of cells in wild-type dorsal root ganglia expressed S1pr3, with S1P activating S1PR3+ thermal nociceptors, indicating a specific role in thermal pain pathways. The study provided insights into the neuronal subtypes and molecular pathways involved in S1P-mediated pain signaling.