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ID 48640
file
creator
Kodama, Keitaro
Tomori, Mizuki
Yoshikawa, Kanade
Saeki, Munenori
Zhang, Fang Fang
subject
REV-ERBs
Chronic pain
Astrocyte
Spinal dorsal horn
Interleukin-1β
Interleukin-6
Tumor necrosis factor
siRNA
abstract
The orphan nuclear receptors REV-ERBα and REV-ERBβ (REV-ERBs) are crucial in the regulation of inflammatory-related gene transcription in astroglioma cells, but their role in nociceptive transduction has yet to be elaborated. Spinal dorsal horn astrocytes contribute to the maintenance of chronic pain. Treatment of cultured spinal astrocytes with specific REV-ERBs agonists SR9009 or GSK4112 significantly prevented lipopolysaccharide (LPS)-induced mRNA upregulation of pronociceptive molecules interleukin-1β (IL-1β) mRNA, interleukin-6 (IL-6) mRNA and matrix metalloprotease-9 (MMP-9) mRNA, but not CCL2 mRNA expression. Treatment with SR9009 also blocked tumor necrosis factor-induced IL-1β mRNA, IL-6 mRNA and MMP-9 mRNA. In addition, treatment with SR9009 significantly blocked LPS-induced upregulation of IL-1β protein, IL-6 protein and MMP-9 activity. The inhibitory effects of SR9009 on LPS-induced expression of pronociceptive molecules were blocked by knockdown of REV-ERBs expression with short interference RNA, confirming that SR9009 exerts its effect through REV-ERBs. Intrathecal LPS treatment in male mice induces hind paw mechanical hypersensitivity, and upregulation of IL-1β mRNA, IL-6 mRNA and glial fibrillary acidic protein (GFAP) expression in spinal dorsal horn. Intrathecal pretreatment of SR9009 prevented the onset of LPS-induced mechanical hypersensitivity, cytokine expression and GFAP expression. Intrathecal injection of SR9009 also ameliorated mechanical hypersensitivity during the maintenance phase of complete Freund’s adjuvant-induced inflammatory pain and partial sciatic nerve ligation-, paclitaxel-, and streptozotocin-induced neuropathy in mice. The current findings suggest that spinal astrocytic REV-ERBs could be critical in the regulation of nociceptive transduction through downregulation of pronociceptive molecule expression. Thus, spinal REV-ERBs could be an effective therapeutic target in the treatment of chronic pain.
description
This work was supported by Grant-in-Aid for Scientific Research (C) grant number 26460342, and grants from the Takeda Science Foundation, Suzuken Memorial Foundation, The Uehara Memorial Foundation and The Nakatomi Foundation. Experiments were carried out using equipment at the Analysis Center of Life Science, Hiroshima University and the Research Center for Molecular Medicine, Faculty of Medicine, Hiroshima University.
journal title
Brain, Behavior, and Immunity
volume
Volume 78
start page
116
end page
130
date of issued
2019-05
publisher
Elsevier
issn
0889-1591
publisher doi
pubmed id
language
eng
nii type
Journal Article
HU type
Journal Articles
DCMI type
text
format
application/pdf
text version
author
rights
© 2019. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/
This is not the published version. Please cite only the published version. この論文は出版社版でありません。引用の際には出版社版をご確認、ご利用ください。
relation url
department
Graduate School of Biomedical & Health Sciences
note
Post-print version/PDF may be used in an institutional repository after an embargo period of 12 months.