Department of Anesthesiology, Ruijin Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, P. R. China ; Department of Anesthesiology, Hang Zhou First People's Hospital, Nan Jing Medical University, Zhejiang, P. R. China.
Department of Anesthesiology, Ruijin Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, P. R. China.
PLoS One. 2014 Jan 21;9(1):e85536. doi: 10.1371/journal.pone.0085536. eCollection 2014.
Cyclin-dependent kinase 5 (Cdk5) has been shown to play an important role in mediating inflammation-induced heat hyperalgesia. However, the underlying mechanism remains unclear. The aim of this study was to determine whether roscovitine, an inhibitor of Cdk5, could reverse the heat hyperalgesia induced by peripheral injection of complete Freund's adjuvant (CFA) via the brain-derived neurotrophic factor (BDNF)-tyrosine kinase B (TrkB) signaling pathway in the dorsal horn of the spinal cord in rats.
Heat hyperalgesia induced by peripheral injection of CFA was significantly reversed by roscovitine, TrkB-IgG, and the TrkB inhibitor K252a, respectively. Furthermore, BDNF was significantly increased from 0.5 h to 24 h after CFA injection in the spinal cord dorsal horn. Intrathecal adminstration of the Cdk5 inhibitor roscovitine had no obvious effects on BDNF levels. Increased TrkB protein level was significantly reversed by roscovitine between 0.5 h and 6 h after CFA injection. Cdk5 and TrkB co-immunoprecipitation results suggested Cdk5 mediates the heat hyperalgesia induced by CFA injection by binding with TrkB, and the binding between Cdk5 and TrkB was markedly blocked by intrathecal adminstration of roscovitine.
Our data suggested that the BDNF-TrkB signaling pathway was involved in CFA-induced heat hyperalgesia mediated by Cdk5. Roscovitine reversed the heat hyperalgesia induced by peripheral injection of CFA by blocking BDNF/TrkB signaling pathway, suggesting that severing the close crosstalk between Cdk5 and the BDNF/TrkB signaling cascade may present a potential target for anti-inflammatory pain.
细胞周期蛋白依赖性激酶 5（Cdk5）已被证明在介导炎症诱导的热痛觉过敏中发挥重要作用。然而，其潜在机制尚不清楚。本研究旨在确定 Cdk5 抑制剂罗克洛维是否可以通过脑源性神经营养因子（BDNF）-酪氨酸激酶 B（TrkB）信号通路逆转完全弗氏佐剂（CFA）外周注射引起的大鼠脊髓背角热痛觉过敏。
罗克洛维、TrkB-IgG 和 TrkB 抑制剂 K252a 分别显著逆转了 CFA 外周注射引起的热痛觉过敏。此外，CFA 注射后 0.5 h 至 24 h，脊髓背角 BDNF 明显增加。鞘内给予 Cdk5 抑制剂罗克洛维对 BDNF 水平无明显影响。CFA 注射后 0.5 h 至 6 h，罗克洛维显著逆转了 TrkB 蛋白水平的增加。Cdk5 和 TrkB 免疫共沉淀结果表明，Cdk5 通过与 TrkB 结合介导 CFA 注射引起的热痛觉过敏，鞘内给予罗克洛维显著阻断了 Cdk5 与 TrkB 之间的结合。
我们的数据表明，BDNF-TrkB 信号通路参与了 Cdk5 介导的 CFA 诱导的热痛觉过敏。罗克洛维通过阻断 BDNF/TrkB 信号通路逆转了 CFA 外周注射引起的热痛觉过敏，表明切断 Cdk5 与 BDNF/TrkB 信号级联之间的紧密串扰可能为抗炎性疼痛提供一个潜在的靶点。
