Department of Anesthesiology, The First Affiliated Hospital of Soochow University, Suzhou City, Jiangsu Province, China.
J Neurosci Res. 2012 Jun;90(6):1249-60. doi: 10.1002/jnr.22815. Epub 2012 Feb 22.
Brain-derived neurotrophic factor (BDNF) released within the spinal cord induces phosphorylation of N-methyl-D-aspartate (NMDA) receptors on the spinal cord neurons. This process is necessary for maintaining pain hypersensitivity after nerve injury. However, little is known about the role of BDNF and NMDA receptors in cancer-induced bone pain (CIBP), whose features are unique. This study demonstrates a critical role of the BDNF-modulated NMDA subunit 1 (NR1) in the induction and maintenance of behavioral hypersensitivity in a rat model of CIBP, both in the spinal cord and in the dorsal root ganglia (DRG). We selectively suppressed BDNF expression by RNA interference (RNAi) using intrathecal administration of BDNF small interfering RNA (siRNA). Then, we assessed mechanical threshold and spontaneous pain in CIBP rats. Real-time PCR, Western blotting, and fluorescent immunohistochemical staining were used to detect BDNF or NR1 both in vivo and in vitro. BDNF and phospho-NR1 were expressed under CIBP experimental conditions, with expression levels peaking at day 6 (BDNF) or 9 (NR1). Intrathecal BDNF siRNA prevented CIBP at an early stage of tumor growth (days 4-6). However, at later stages (days 10-12), intrathecal BDNF siRNA only attenuated, but did not completely block, the established CIBP. BDNF-induced NMDA receptor activation in the spinal cord or DRG leads to central sensitization and behavioral hypersensitivity. Thus, BDNF might provide a targeting opportunity for alleviating CIBP.
脑源性神经营养因子 (BDNF) 在脊髓内释放，会导致脊髓神经元上 N-甲基-D-天冬氨酸 (NMDA) 受体的磷酸化。这一过程对于维持神经损伤后的痛觉过敏是必需的。然而，对于癌症引起的骨痛（CIBP）中 BDNF 和 NMDA 受体的作用，人们知之甚少，因为 CIBP 具有独特的特征。本研究表明，BDNF 调节的 NMDA 亚基 1（NR1）在 CIBP 大鼠模型的脊髓和背根神经节（DRG）中诱导和维持行为性敏化中起关键作用。我们通过鞘内给予 BDNF 小干扰 RNA（siRNA）选择性地抑制 BDNF 表达，然后评估 CIBP 大鼠的机械阈值和自发性疼痛。实时 PCR、Western blot 和荧光免疫组织化学染色用于检测体内和体外的 BDNF 或 NR1。BDNF 和磷酸化 NR1 在 CIBP 实验条件下表达，表达水平在第 6 天（BDNF）或第 9 天（NR1）达到峰值。鞘内 BDNF siRNA 可在肿瘤生长的早期预防 CIBP，但在后期（第 10-12 天），鞘内 BDNF siRNA 仅减弱但不能完全阻断已建立的 CIBP。BDNF 在脊髓或 DRG 中诱导 NMDA 受体激活，导致中枢敏化和行为性敏化。因此，BDNF 可能为缓解 CIBP 提供了一个靶向机会。
