Author Response: 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, finding that S1PR3 knockout mice showed reduced sensitivity to mechanical stimuli. S1P was found to modulate the excitability of A-delta mechanonociceptors by affecting KCNQ2/3 channels, suggesting that S1P signaling sets mechanical pain thresholds through baseline activity. Despite addressing some criticisms, such as potential developmental effects in knockout mice and characterizing S1PR3 expression in specific neurons, the study faced unresolved issues regarding previous research overlaps and weak evidence for Kv7 channel inhibition, leading to its non-acceptance for publication. The research provided insights into S1P's role in pain modulation, distinct from prior studies on small diameter and capsaicin-sensitive neurons.