Brain-derived neurotrophic factor contributes to spinal long-term potentiation and mechanical hypersensitivity by activation of spinal microglia in rat
Brain-derived neurotrophic factor contributes to spinal long-term potentiation and mechanical hypersensitivity by activation of spinal microglia in rat
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DOI：
10.1016/j.bbi.2010.09.025
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发表时间：
2011-02
期刊：
影响因子：
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通讯作者：
Li-Jun Zhou;Tao-tao Yang;Xiao Wei;Yong Liu;Wen-Jun Xin;Yuan Chen;R. Pang;Y. Zang;Yongyong Li;Xian-Guo Liu
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文献类型：
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作者：
Li-Jun Zhou;Tao-tao Yang;Xiao Wei;Yong Liu;Wen-Jun Xin;Yuan Chen;R. Pang;Y. Zang;Yongyong Li;Xian-Guo Liu
已有研究表明，周围神经损伤后，激活的小胶质细胞释放的脑源性神经营养因子(BDNF)参与了神经病理性疼痛，但BDNF是否影响小胶质细胞的功能尚不清楚。在目前的工作中，我们发现脊髓应用BDNF可以激活幼稚动物的脊髓小胶质细胞，而小胶质细胞抑制剂米诺环素则阻断了BDNF诱导的长时程增强。此外，在BDNF诱导LTP后，磷酸化的Src家族激酶(p-SFKs)和磷酸化的p38丝裂原活化蛋白激酶(p-p38 MAPK)仅在脊髓小胶质细胞中上调，而在神经元和星形胶质细胞中不表达，而脊髓应用SFKs抑制剂(PP2或SU6656)或p38MAPK抑制剂(SB203580)可阻断BDNF诱导的LTP并抑制小胶质细胞的激活。由于脊髓C纤维突触的LTP被认为是神经病理性疼痛的基础，我们随后利用备用神经损伤(SNI)模型研究了BDNF是否通过激活脊髓小胶质细胞而参与了机械超敏反应。SNI后，BDNF和TrkB受体主要在背角神经元和激活的小胶质细胞表达上调，而p-SFKs和p-p38MAPK仅在小胶质细胞表达上调。SNI前鞘内注射BDNF清除剂TrkB-Fc，可阻止神经病理性疼痛的行为体征，并抑制SNI引起的小胶质细胞活化和p-SFKs、p-p38MAPK的上调。因此，脊髓背角BDNF/TrkB信号的增加可能通过激活周围神经损伤后的小胶质细胞而参与神经病理性疼痛，抑制SFKs或p38MAPK可能选择性地抑制脊髓背角的小胶质细胞。
It has been shown that following peripheral nerve injury brain-derived neurotrophic factor (BDNF) released by activated microglia contributes to neuropathic pain, but whether BDNF affects the function of microglia is still unknown. In the present work we found that spinal application of BDNF, which induced long-term potentiation (LTP) of C-fiber evoked field potentials, activated spinal microglia in naïve animals, while pretreatment with microglia inhibitor minocycline blocked BDNF-induced LTP. In addition, following LTP induction by BDNF, both phosphorylated Src-family kinases (p-SFKs) and phosphorylated p38 mitogen-activated protein kinase (p-p38 MAPK) were up-regulated only in spinal microglia but not in neurons and astrocytes, whilst spinal application of SFKs inhibitor (PP2 or SU6656) or p38 MAPK inhibitor (SB203580) blocked BDNF-induced LTP and suppressed microglial activation. As spinal LTP at C-fiber synapses is considered to underlie neuropathic pain, we subsequently examined whether BDNF may contribute to mechanical hypersensitivity by activation of spinal microglia using spared nerve injury (SNI) model. Following SNI BDNF and TrkB receptor were up-regulated mainly in dorsal horn neurons and in activated microglia, and p-SFKs and p-p38 MAPK were increased exclusively in microglia. Intrathecal injection of BDNF scavenger TrkB-Fc starting before SNI, which prevented the behavioral sign of neuropathic pain, suppressed both microglial activation and the up-regulation of p-SFKs and p-p38 MAPK produced by SNI. Thus, the increased BDNF/TrkB signaling in spinal dorsal horn may contribute to neuropathic pain by activation of microglia following peripheral nerve injury and inhibition of SFKs or p38 MAPK may selectively inhibit microglia in spinal dorsal horn.