ERK MAP kinase activation in spinal cord regulates phosphorylation of Cdk5 at serine 159 and contributes to peripheral inflammation induced pain/hypersensitivity.
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.
Department of Anesthesia, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China.
Xiaoqin
X
Zhang
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.
Honghai
H
Zhang
Department of Anesthesia, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China.
Haijun
H
Shao
Department of Anesthesia, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China.
Qingsheng
Q
Xue
Department of Anesthesia, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China.
Buwei
B
Yu
D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D005404:Fixatives / Q000009:adverse effects / Q000494:pharmacology; D005557:Formaldehyde / Q000009:adverse effects / Q000494:pharmacology; D006930:Hyperalgesia / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D020935:MAP Kinase Signaling System; D008297:Male; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009474:Neurons / Q000201:enzymology / Q000473:pathology; D009570:Nitriles / Q000494:pharmacology; D010146:Pain / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077546:Roscovitine
D002070:Butadienes; D005404:Fixatives; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011687:Purines; C113580:U 0126; D000077546:Roscovitine; D005557:Formaldehyde; D051360:Cyclin-Dependent Kinase 5; C495907:Cdk5 protein, rat; D048052:Mitogen-Activated Protein Kinase 3