Brain-derived neurotrophic factor increases in the uninjured dorsal root ganglion neurons in selective spinal nerve ligation model
Brain-derived neurotrophic factor increases in the uninjured dorsal root ganglion neurons in selective spinal nerve ligation model
复制标题
DOI：
10.1523/jneurosci.21-13-04891.2001
复制
发表时间：
2001-07-01
影响因子：
5.3
通讯作者：
Noguchi, K
中科院分区：
文献类型：
--
作者：
Fukuoka, T;Kondo, E;Noguchi, K
神经生长因子（NGF）和脑源性神经营养因子（BDNF）是神经营养蛋白家族的两个主要成员。使用免疫组织化学和原位杂交组织化学，我们检查了 L5 脊神经结扎 (SPNL)（一种神经性疼痛模型）对未受伤的 L4 背根神经节 (DRG) 中 BDNF 表达的影响。 L5 SPNL 后，BDNF 的免疫反应性和 BDNF mRNA 的杂交强度主要在中小型神经元中增加。从结扎后第3天到第28天，与对侧DRG相比，同侧L4 DRG中表达BDNF mRNA的神经元的百分比增加。结扎后 14 天，同侧 L4 DRG 中观察到的 BDNF 免疫反应性神经元数量明显多于对侧。为了测试BDNF对该模型中产生的热痛觉过敏的贡献，我们在结扎后第三天鞘内注射抗BDNF抗体。这种治疗在几个小时内明显减弱了热痛觉过敏。几乎所有表达 BDNF mRNA 的神经元都共表达 trkA（一种高亲和力 NGF 受体 mRNA）。连接后14天，同侧L4 DRG中trkA细胞的BDNF mRNA表达细胞百分比显着增加。此外，我们使用 ELISA、Northern 印迹分析和抗 NGF 抗体检查了 NGF 对这种表型变化的贡献。 L5 SPNL后14天，同侧L4 DRG中NGF含量线性增加并达到统计学显着水平。此外，在该时间点，在同侧L5 DRG和坐骨神经中观察到NGF mRNA增加，但在同侧L4 DRG或L4脊神经中没有观察到NGF mRNA增加。将抗 NGF 抗体局部应用于 L5 脊神经结扎部位旁边的 L4 脊神经，可在结扎后 5 天内防止热痛觉过敏的发生。我们的数据表明，在未受伤的 L4 DRG 神经元中增加的 BDNF 充当背角的感觉神经调节剂，并有助于这种神经性疼痛模型中的热痛觉过敏。局部合成的 NGF 对热痛觉过敏的贡献也得到了证明。未损伤的 DRG 神经元中 BDNF 和 NGF 表达和含量的这些动态变化可能与神经病理性疼痛的病理机制有关。
Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are two major members of the neurotrophin family. Using immunohistochemistry and in situ hybridization histochemistry, we examined the effect of L5 spinal nerve ligation (SPNL), a neuropathic pain model, on the expression of BDNF in the uninjured L4 dorsal root ganglion (DRG). After L5 SPNL, both immunoreactivity for BDNF and the hybridization intensity for BDNF mRNA increased mainly in the small- and medium-sized neurons. The percentage of BDNF mRNA-expressing neurons increased in the ipsilateral L4 DRG compared with the contralateral DRG from the third to 28th day after ligation. A significantly greater number of BDNF-immunoreactive neurons were observed in the ipsilateral L4 DRG than contralateral side 14 d after ligation. To test the contribution of BDNF to the thermal hyperalgesia produced in this model, we intrathecally injected anti-BDNF antibody at third day after ligation. This treatment clearly attenuated thermal hyperalgesia for a few hours. Almost all BDNF mRNA-expressing neurons coexpressed trkA, a high-affinity NGF receptor, mRNA. The percentage of BDNF mRNA-expressing cells of trkA cells significantly increased in the ipsilateral L4 DRG 14 d after ligation. Furthermore, we examined the contribution of NGF on this phenotypic change using ELISA, Northern blot analysis, and anti-NGF antibody. NGF content in the ipsilateral L4 DRG linearly increased and reached a statistical significant level 14 d after L5 SPNL. Moreover, at this time point, the increase in NGF mRNA was observed in the ipsilateral L5 DRG and sciatic nerve, but not in the ipsilateral L4 DRG or L4 spinal nerve. Local application of anti-NGF antibody to the L4 spinal nerve beside the L5 spinal nerve-ligation site prevented the development of thermal hyperalgesia for 5 d after ligation. Our data suggest that BDNF, which increased in the uninjured L4 DRG neurons, acts as a sensory neuromodulator in the dorsal horn and contributes to thermal hyperalgesia in this neuropathic pain model. The contribution of locally synthesized NGF to thermal hyperalgesia was also demonstrated. These dynamic alterations in the expression and content of BDNF and NGF in the uninjured DRG neurons might be involved in the pathomechanisms of neuropathic pain.