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

The study examined the role of sphingosine 1-phosphate (S1P) and its receptor S1PR3 in mechanical pain regulation. It found that S1PR3 knockout mice had reduced sensitivity to mechanical pain, indicating that S1P/S1PR3 signaling sets baseline mechanical pain thresholds. S1P was shown to affect A-delta mechanonociceptor excitability by modulating KCNQ2/3 channels. Despite initial criticisms regarding previous research overlaps and weak evidence for ionic mechanisms, the study provided significant insights into the molecular mechanisms of mechanical pain, suggesting that while baseline S1P levels regulate mechanical pain, elevated levels during inflammation promote heat hypersensitivity. The research addressed criticisms with new data, confirming the involvement of KCNQ2/3 channels and clarifying S1P's effects on neurons.