The signaling lipid sphingosine 1-phosphate regulates mechanical pain

Abstract
Data availability
Article and author information

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

The following previously published data sets were used

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Available upon request.

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0055001
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Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE59739).

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE59739

Article and author information

Author details

Rose Z Hill

Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States

Competing interests
The authors declare that no competing interests exist.
Benjamin U Hoffman

Department of Physiology and Cellular Biophysics, Columbia University, New York, United States

Competing interests
The authors declare that no competing interests exist.
Takeshi Morita

Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-8570-6744
Stephanie M Campos

Neurobiology Course, Marine Biological Laboratory, Woods Hole, United States

Competing interests
The authors declare that no competing interests exist.
Ellen A Lumpkin

Department of Physiology and Cellular Biophysics, Columbia University, New York, United States

Competing interests
The authors declare that no competing interests exist.
Rachel B Brem

Department of Plant and Microbial Biology, University of California, Berkeley, Berkeley, United States

Competing interests
The authors declare that no competing interests exist.
Diana M Bautista

Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States

For correspondence
dbautista@berkeley.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-6809-8951

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

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.