title: Cdk5 contributes to inflammation-induced thermal hyperalgesia mediated by the p38 MAPK pathway in microglia.
abstract: BACKGROUND
  The mechanisms underlying cyclin-dependent kinase 5 (Cdk5)-mediated thermal hyperalgesia induced by inflammation remain poorly understood. In the present study, we examined thermal hyperalgesia provoked by peripheral injection of complete Freund׳s adjuvant (CFA) to test for Cdk5 signaling in the spinal dorsal horns of rats through the p38 mitogen-activated protein kinase (p38 MAPK) signaling pathway, which is known to function in mediating inflammatory pain.
  
  
  METHODS
  We induced the inflammatory pain model by plantar injection of CFA and compared the inhibitory effects of roscovitine and SB203580 on thermal hyperalgesia. We measured localization of Cdk5, p35, OX-42, and glial fibrillary acidic protein (GFAP) in the dorsal horn at 1 and 3 days after CFA injection using immunohistochemistry, and we measured protein levels of OX-42 and phosphorylated-p38 (p-p38) using Western blot analysis. Tumor necrosis factor-a (TNF-a) was measured by ELISA.
  
  
  RESULTS
  The maximum thermal hyperalgesia induced by CFA occurred at 1d following injection and decreased until 5 d. We found colocalization of the Cdk5 activator p35, the microglial marker OX-42 and p-p38 in the same microglial cells and neurons of the spinal cord at day 1 after CFA injection; however, we saw no colocalization of p35 and GFAP, a marker of activated astrocytes. The thermal hyperalgesia induced by CFA was inhibited by intrathecal administration of the Cdk5 inhibitor roscovitine and by the p38 inhibitor SB203580. Furthermore, the expression of OX-42, p-p38, and TNF-a was remarkably increased from days 1 to 5 post-CFA injection and were significantly reversed by roscovitine between 1 and 3 days.
  
  
  CONCLUSIONS
  Cdk5, an upstream regulator of p38 and TNF-a, mediates CFA-induced thermal hyperalgesia. As such, pharmacological blocking of the generation of p-p38 mediated by Cdk5 may present a novel approach for diminishing inflammatory pain. This article is part of a Special Issue entitled SI: Spinal cord injury.
authors.affiliation: Department of Anesthesiology, Hangzhou First People׳s Hospital, Nanjing Medical University, Zhejiang, PR China.
authors.lastname: Fang-Hu
authors.affiliation: Department of Anesthesiology, Hangzhou First People׳s Hospital, Nanjing Medical University, Zhejiang, PR China. Electronic address: zhanghonghai_0902@163.com.
authors.forename: Hong-Hai
authors.initials: HH
authors.lastname: Zhang
authors.affiliation: Vascular and Interventional Radiology Translational Laboratory, Department of Radiology, Mayo Clinic, Rochester, MN, USA. Electronic address: yang8403@sina.com.
authors.forename: Bin-Xia
authors.initials: BX
authors.lastname: Yang
authors.affiliation: Department of Pharmacy, the Sixth Affiliated Hospital of Shanghai JiaoTong University School of Medicine, Shanghai, PR China.
authors.forename: Jin-Lu
authors.initials: JL
authors.lastname: Huang
authors.affiliation: Department of Anesthesiology, Hangzhou First People׳s Hospital, Nanjing Medical University, Zhejiang, PR China.
authors.forename: Jian-Liang
authors.initials: JL
authors.lastname: Shun
authors.affiliation: Department of Anesthesiology, Hangzhou First People׳s Hospital, Nanjing Medical University, Zhejiang, PR China.
authors.forename: Fei-Juan
authors.initials: FJ
authors.lastname: Kong
authors.affiliation: Department of Anesthesiology, Hangzhou First People׳s Hospital, Nanjing Medical University, Zhejiang, PR China.
authors.lastname: Peng-Xu
authors.affiliation: Department of Thoracic Surgery, Children׳s Hospital of He Bei Province, ShiJiaZhuang, PR China.
authors.forename: Zhi-Guo
authors.initials: ZG
authors.lastname: Chen
authors.affiliation: Department of Pharmacy, Children׳s Hospital of Fudan University, Shanghai, PR China.
authors.forename: Jin-Miao
authors.initials: JM
authors.lastname: Lu
mesh_terms: D000818:Animals; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005620:Freund's Adjuvant; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D008297:Male; D017628:Microglia / Q000378:metabolism*; D009187:Myelitis / Q000139:chemically induced / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D011687:Purines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077546:Roscovitine; D066148:Spinal Cord Dorsal Horn / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D007093:Imidazoles; D011687:Purines; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D000077546:Roscovitine; D005620:Freund's Adjuvant; D051360:Cyclin-Dependent Kinase 5; C495907:Cdk5 protein, rat; C093642:SB 203580
keywords: Cdk5; Hyperalgesia; Inflammatory pain; OX-42; P38; Roscovitine; TNF-a