Inhibition of the Rho/Rho kinase pathway prevents lipopolysaccharide-induced hyperalgesia and the release of TNF-α and IL-1β in the mouse spinal cord

Cunjin Wang; Siyuan Song; Yang Zhang; Yali Ge; Xiangzhi Fang; Tianfeng Huang; Jin Du; Ju Gao

doi:10.1038/srep14553

Inhibition of the Rho/Rho kinase pathway prevents lipopolysaccharide-induced hyperalgesia and the release of TNF-α and IL-1β in the mouse spinal cord

Sci Rep. 2015 Sep 29:5:14553. doi: 10.1038/srep14553.

Authors

Cunjin Wang¹, Siyuan Song², Yang Zhang¹, Yali Ge¹, Xiangzhi Fang¹, Tianfeng Huang¹, Jin Du¹, Ju Gao¹

Affiliations

¹ Clinical Medical College of Yangzhou University &Department of Anesthesiology, Subei People's Hospital of Jiangsu Province, Yangzhou, China.
² Jiangsu Key Laboratory of Anesthesiology &Jiangsu Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical College, Xuzhou, China.

Abstract

Administration of lipopolysaccharide (LPS) by various routes produces profound inflammatory pain hypersensitivity. However, the molecular events that induce this response remain largely uncharacterized. In the present study, we sought to elucidate the role of the Rho/Rho kinase (ROCK) pathway in the release of tumor necrosis factor-α (TNF-α) and interleukin 1β (IL-1β) following injection of LPS into the mouse paw, which is associated with nociceptive behavior. The spinal cord of LPS-treated mice showed increased active GTP-bound RhoA and upregulation of ROCK2 and c-fos compared to the normal saline group. Furthermore, the inflammation-related cytokines TNF-α and IL-1β were markedly increased in the spinal dorsal horn after intraplantar injection of LPS. However, the latter effects were prevented by prophylactic intrathecal administration of the Rho inhibitor (C3 exoenzyme) or the ROCK inhibitor (Y27632). Collectively, our results suggest that the Rho/ROCK signaling pathway plays a critical role in LPS-induced inflammatory pain and that this pathway is coincident with the release of the pro-nociceptive cytokines TNF-α and IL-1β, which produces hyperalgesia.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ADP Ribose Transferases / pharmacology*
Amides / pharmacology*
Animals
Botulinum Toxins / pharmacology*
Gene Expression Regulation
Hindlimb
Hot Temperature
Hyperalgesia / chemically induced
Hyperalgesia / genetics
Hyperalgesia / physiopathology
Hyperalgesia / prevention & control*
Injections, Spinal
Interleukin-1beta / antagonists & inhibitors*
Interleukin-1beta / genetics
Interleukin-1beta / metabolism
Lipopolysaccharides
Male
Mice
Mice, Inbred C57BL
Nociception / physiology
Pain Measurement
Proto-Oncogene Proteins c-fos / genetics
Proto-Oncogene Proteins c-fos / metabolism
Pyridines / pharmacology*
Signal Transduction
Spinal Cord Dorsal Horn
Tumor Necrosis Factor-alpha / antagonists & inhibitors*
Tumor Necrosis Factor-alpha / genetics
Tumor Necrosis Factor-alpha / metabolism
rho GTP-Binding Proteins / antagonists & inhibitors*
rho GTP-Binding Proteins / genetics
rho GTP-Binding Proteins / metabolism
rho-Associated Kinases / antagonists & inhibitors*
rho-Associated Kinases / genetics
rho-Associated Kinases / metabolism
rhoA GTP-Binding Protein

Substances

Amides
Interleukin-1beta
Lipopolysaccharides
Proto-Oncogene Proteins c-fos
Pyridines
Tumor Necrosis Factor-alpha
Y 27632
ADP Ribose Transferases
exoenzyme C3, Clostridium botulinum
Rock2 protein, mouse
rho-Associated Kinases
Botulinum Toxins
RhoA protein, mouse
rho GTP-Binding Proteins
rhoA GTP-Binding Protein