ERK MAP kinase activation in spinal cord regulates phosphorylation of Cdk5 at serine 159 and contributes to peripheral inflammation induced pain/hypersensitivity

Xiaoqin Zhang; Honghai Zhang; Haijun Shao; Qingsheng Xue; Buwei Yu

doi:10.1371/journal.pone.0087788

ERK MAP kinase activation in spinal cord regulates phosphorylation of Cdk5 at serine 159 and contributes to peripheral inflammation induced pain/hypersensitivity

PLoS One. 2014 Jan 31;9(1):e87788. doi: 10.1371/journal.pone.0087788. eCollection 2014.

Authors

Xiaoqin Zhang¹, Honghai Zhang², Haijun Shao¹, Qingsheng Xue¹, Buwei Yu¹

Affiliations

¹ Department of Anesthesia, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China.
² Department of Anesthesia, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China ; Department of Anesthesia, Hangzhou First People's Hospital, Nanjing Medical University, Zhejiang, P.R. China.

Abstract

Cyclin-dependent kinase 5 is a proline-directed serine/threonine kinase and its activity participates in the regulation of nociceptive signaling. Like binding with the activators (P35 or P25), the phosphorylation of Cdk5 plays a critical role in Cdk5 activation. However, it is still unclear whether Cdk5 phosphorylation (p-Cdk5) contributes to pain hyperalgesia. The aim of our current study was to identify the roles of p-Cdk5 and its upstream regulator in response to peripheral inflammation. Complete Freund's adjuvant (CFA) injection induced acute peripheral inflammation and heat hyperalgesia, which was accompanied by sustained increases in phospho-ERK1/2 (p-ERK1/2) and phospho-Cdk5(S159) (p-Cdk5(S159)) in the spinal cord dorsal horn (SCDH). CFA-induced p-ERK primarily colocalized with p-Cdk5(S159) in superficial dorsal horn neurons. Levels in p-ERK and p-Cdk5 were also increased in the 2(nd) phase of hyperalgesia induced by formalin injection, which can produce acute and tonic inflammatory pain. MAP kinase kinase inhibitor U0126 intrathecal delivery significantly suppressed the elevation of p-Cdk5(S159), Cdk5 activity and pain response behavior (Heat hyperalgesia, Spontaneous flinches) induced by CFA or formalin injection. Cdk5 inhibitor roscovitine intrathecal administration also suppressed CFA-induced heat hyperalgesia and Cdk5 phosphorylation, but did not attenuate ERK activation. All these findings suggested that p-Cdk5(S159) regulated by ERK pathway activity may be a critical mechanism involved in the activation of Cdk5 in nociceptive spinal neurons contributes to peripheral inflammatory pain hypersensitivity.

Publication types

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

MeSH terms

Animals
Butadienes / pharmacology
Cyclin-Dependent Kinase 5 / metabolism*
Enzyme Activation / drug effects
Fixatives / adverse effects
Fixatives / pharmacology
Formaldehyde / adverse effects
Formaldehyde / pharmacology
Hyperalgesia / chemically induced
Hyperalgesia / enzymology*
Hyperalgesia / pathology
MAP Kinase Signaling System*
Male
Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
Mitogen-Activated Protein Kinase 3 / metabolism*
Neurons / enzymology
Neurons / pathology
Nitriles / pharmacology
Pain / chemically induced
Pain / enzymology*
Pain / pathology
Phosphorylation / drug effects
Protein Kinase Inhibitors / pharmacology
Purines / pharmacology
Rats
Rats, Sprague-Dawley
Roscovitine

Substances

Butadienes
Fixatives
Nitriles
Protein Kinase Inhibitors
Purines
U 0126
Roscovitine
Formaldehyde
Cyclin-Dependent Kinase 5
Cdk5 protein, rat
Mitogen-Activated Protein Kinase 3

Grants and funding

This work was supported by National Natural Science Foundation, Beijing, P.R. China, grant No. 81072703 and No. 81373492 to Dr. Buwei Yu (http://www.nsfc.gov.cn/Portal0/default152.htm). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.