BDNF contributes to the development of neuropathic pain by induction of spinal long-term potentiation via SHP2 associated GluN2B-containing NMDA receptors activation in rats with spinal nerve ligation
BDNF contributes to the development of neuropathic pain by induction of spinal long-term potentiation via SHP2 associated GluN2B-containing NMDA receptors activation in rats with spinal nerve ligation
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BDNF 通过在脊髓神经结扎大鼠中激活 SHP2 相关的含有 GluN2B 的 NMDA 受体来诱导脊髓长时程增强，从而促进神经性疼痛的发展
DOI：
10.1016/j.nbd.2014.10.025
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发表时间：
2015-01-01
影响因子：
6.1
通讯作者：
Xing, Guo-Gang
中科院分区：
文献类型：
--
作者：
Ding, Xu;Cai, Jie;Xing, Guo-Gang
神经性疼痛的致病机制在很大程度上仍然是未知的。在这项研究中，我们研究了脊髓BDNF是否通过Src同源-2结构域蛋白酪氨酸磷酸酶-2 （SHP2）磷酸化激活GluN2B-NMDA受体，从而在脊髓神经结扎（SNL）后大鼠的背角LTP诱导和神经性疼痛的发生。我们首先证明脊髓BDNF参与了完整和SNL大鼠背角WDR神经元的长期高兴奋性（即中枢致敏）以及疼痛异常性痛的发展。其次，我们发现BDNF通过上调脊髓背角GluN2B-NMDA受体的功能诱导c -纤维突触的脊髓LTP，并且这种BDNF介导的LTP样状态是SNL大鼠坐骨神经高频电刺激（HFS）引起的脊髓LTP闭塞的原因。最后，我们验证了bdnf诱发的SHP2磷酸化是随后GluN2B-NMDA受体上调和脊髓LTP诱导以及疼痛异常性痛发展所必需的。利用强效的SHP2蛋白酪氨酸磷酸酶抑制剂NSC-87877阻断脊髓背角SHP2磷酸化，或通过鞘内递送SHP2 siRNA敲低脊髓SHP2，不仅可以阻止bdnf介导的GluN2B-NMDA受体的激活、完整大鼠脊髓LTP的诱导和疼痛异位性疼痛的诱发，还可以减少snl诱发的GluN2B-NMDA受体的上调和脊髓LTP的阻断，最终缓解神经症大鼠的疼痛异位性疼痛。综上所述，这些结果表明BDNF/SHP2/GluN2B-NMDA信号级联在周围神经损伤后中枢致敏和神经性疼痛的发展中起着至关重要的作用。(C) 2015 Elsevier Inc .版权所有
The pathogenic mechanisms underlying neuropathic pain still remain largely unknown. In this study, we investigated whether spinal BDNF contributes to dorsal horn LTP induction and neuropathic pain development by activation of GluN2B-NMDA receptors via Src homology-2 domain-containing protein tyrosine phosphatase-2 (SHP2) phosphorylation in rats following spinal nerve ligation (SNL). We first demonstrated that spinal BDNF participates in the development of long-lasting hyperexcitability of dorsal horn WDR neurons (i.e. central sensitization) as well as pain allodynia in both intact and SNL rats. Second, we revealed that BDNF induces spinal LTP at C-fiber synapses via functional up-regulation of GluN2B-NMDA receptors in the spinal dorsal horn, and this BDNF-mediated LTP-like state is responsible for the occlusion of spinal LTP elicited by subsequent high-frequency electrical stimulation (HFS) of the sciatic nerve in SNL rats. Finally, we validated that BDNF-evoked SHP2 phosphorylation is required for subsequent GluN2B-NMDA receptors up-regulation and spinal LTP induction, and also for pain allodynia development. Blockade of SHP2 phosphorylation in the spinal dorsal horn using a potent SHP2 protein tyrosine phosphatase inhibitor NSC-87877, or knockdown of spinal SHP2 by intrathecal delivery of SHP2 siRNA, not only prevents BDNF-mediated GluN2B-NMDA receptors activation as well as spinal LTP induction and pain allodynia elicitation in intact rats, but also reduces the SNL-evoked GluN2B-NMDA receptors up-regulation and spinal LTP occlusion, and ultimately alleviates pain allodynia in neuropathic rats. Taken together, these results suggest that the BDNF/SHP2/GluN2B-NMDA signaling cascade plays a vital role in the development of central sensitization and neuropathic pain after peripheral nerve injury. (C) 2015 Elsevier Inc All rights reserved.