RT Journal Article
SR Electronic
T1 The signaling lipid sphingosine 1-phosphate regulates mechanical pain
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 236778
DO 10.1101/236778
A1 Rose Z. Hill
A1 Benjamin Hoffman
A1 Takeshi Morita
A1 Stephanie M. Campos
A1 Ellen A. Lumpkin
A1 Rachel B. Brem
A1 Diana M. Bautista
YR 2017
UL http://biorxiv.org/content/early/2017/12/19/236778.abstract
AB Somatosensory neurons mediate responses to diverse mechanical stimuli, from innocuous touch to noxious pain. While recent studies have identified distinct populations of A mechanonociceptors (AMs) that are required for mechanical pain, the molecular underpinnings of mechanonociception remain unknown. Here, we show that the bioactive lipid sphingosine 1-phosphate (S1P) and S1P Receptor 3 (S1PR3) are critical regulators of acute mechanonociception. Genetic or pharmacological ablation of S1PR3, or blockade of S1P production, significantly impaired the behavioral response to noxious mechanical stimuli, with no effect on responses to innocuous touch or thermal stimuli. These effects are mediated by fast-conducting Aδ mechanonociceptors, which displayed a significant decrease in mechanosensitivity in S1PR3 mutant mice. We show that S1PR3 signaling tunes mechanonociceptor excitability via modulation of KCNQ2/3 channels. Our findings define a new role for S1PR3 in regulating neuronal excitability and establish the importance of S1P/S1PR3 signaling in the setting of mechanical pain thresholds.