Zhang, F, Gigout, S orcid.org/0000-0002-2966-8843, Liu, Y et al. (6 more authors) (2019) Repressor element 1-silencing transcription factor drives the development of chronic pain states. Pain, 160 (10). pp. 2398-2408. ISSN 0304-3959
Abstract
Chronic pain is an unmet clinical problem with vast individual, societal and economic impact. Pathologic activity of the peripheral somatosensory afferents is one of the major drivers of chronic pain. This overexcitable state of somatosensory neurons is, in part, produced by the dysregulation of genes controlling neuronal excitability. Despite intense research, a unifying theory behind neuropathic remodelling is lacking. Here we show that transcriptional suppressor, repressor element 1-silencing transcription factor (REST, NRSF), is necessary and sufficient for the development of hyperalgesic state following chronic nerve injury or inflammation. Viral overexpression of REST in mouse DRG induced prominent mechanical and thermal hyperalgesia in vivo. Sensory neuron specific, inducible Rest knock-out prevented the development of such hyperalgesic state in three different chronic pain models. Genetic deletion of Rest reverted injury-induced hyperalgesia. Moreover, viral overexpression of REST in the same neurons in which its gene has been genetically deleted restored neuropathic hyperalgesia. Finally, sensory neuron specific Rest knockout prevented injury-induced downregulation of REST target genes in DRG neurons. This work identified REST as a major regulator of peripheral somatosensory neuron remodelling leading to chronic pain. The findings might help to develop a novel therapeutic approaches to combat chronic pain.This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Metadata
Item Type: | Article |
---|---|
Authors/Creators: |
|
Copyright, Publisher and Additional Information: | © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain. This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
Keywords: | Chronic pain; Epigenetics; K1 channel; Repressor element 1–silencing transcription factor; REST; NRSF |
Dates: |
|
Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Biomedical Sciences (Leeds) |
Funding Information: | Funder Grant number MRC G1002183/1 |
Depositing User: | Symplectic Publications |
Date Deposited: | 25 Jun 2019 13:54 |
Last Modified: | 06 Oct 2019 09:25 |
Status: | Published |
Publisher: | Elsevier |
Identification Number: | 10.1097/j.pain.0000000000001633 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:147700 |