The signaling lipid sphingosine 1-phosphate regulates mechanical pain
- University of California, Berkeley, United States
- Columbia University, United States
- Marine Biological Laboratory, United States
Abstract
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 A 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.
Data availability
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Unbiased classification of sensory neuron types by large-scale single-cell RNA sequencingPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE59739).
Article and author information
Author details
Funding
National Institute of Neurological Disorders and Stroke (NS077224)
- Rachel B Brem
- Diana M Bautista
National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR059385)
- Diana M Bautista
National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR051219)
- Ellen A Lumpkin
National Institute of Neurological Disorders and Stroke (NS105449)
- Benjamin U Hoffman
National Institute of General Medical Sciences (GM007367)
- Benjamin U Hoffman
Howard Hughes Medical Institute (Faculty Scholar Award)
- Diana M Bautista
National Institute of Neurological Disorders and Stroke (NS098097)
- Rachel B Brem
- Diana M Bautista
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All experiments were performed under the policies and recommendations of the International Association for the Study of Pain and approved by the University of California, Berkeley Animal Care and Use Committee (Protocol Number: AUP-2017-02-9550).
Copyright
© 2018, Hill et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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The signaling lipid sphingosine 1-phosphate regulates mechanical pain
eLife 7:e33285.
https://doi.org/10.7554/eLife.33285
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