Brain-derived neurotrophic factor modulates N-methyl-D-aspartate receptor activation in a rat model of cancer-induced bone pain
Brain-derived neurotrophic factor modulates N-methyl-D-aspartate receptor activation in a rat model of cancer-induced bone pain
复制标题
脑源性神经营养因子调节癌症引起的骨痛大鼠模型中 N-甲基-D-天冬氨酸受体的激活
DOI：
10.1002/jnr.22815
复制
发表时间：
2012-06-01
影响因子：
4.2
通讯作者：
Zuo, Jian-Ling
中科院分区：
文献类型：
--
作者：
Wang, Li-Na;Yang, Jian-Ping;Zuo, Jian-Ling
脊髓内释放的脑源性神经营养因子（BDNF）诱导脊髓神经元上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疼痛超敏性是必要的。然而，BDNF和NMDA受体在癌症引起的骨痛（cancer-induced bone pain，CIBP）中的作用却知之甚少。这项研究表明，在CIBP大鼠模型中，在脊髓和背根神经节（DRG）中，BDNF调节的NMDA亚基1（NR 1）在诱导和维持行为超敏反应中起着关键作用。我们选择性地抑制BDNF表达的RNA干扰（RNAi）使用鞘内给药的BDNF小干扰RNA（siRNA）。然后，我们评估了CIBP大鼠的机械阈值和自发痛。采用实时荧光定量PCR、Western blotting和荧光免疫组织化学染色方法检测BDNF和NR 1在体内和体外的表达。BDNF和磷酸化NR 1在CIBP实验条件下表达，表达水平在第6天（BDNF）或第9天（NR 1）达到峰值。鞘内BDNF siRNA在肿瘤生长的早期阶段（第46天）阻止CIBP。然而，在后期阶段（10 - 12天），鞘内BDNF siRNA仅减弱，但没有完全阻断已建立的CIBP。BDNF诱导的脊髓或DRG中的NMDA受体活化导致中枢敏化和行为超敏反应。因此，BDNF可能为缓解CIBP提供靶向机会。(c)2012 Wiley Priodicals，Inc.
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 46). However, at later stages (days 1012), 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. (c) 2012 Wiley Priodicals, Inc.