BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain
BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain
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DOI：
10.1038/nature04223
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发表时间：
2005-12-15
期刊：
影响因子：
64.8
通讯作者：
De Koninck, Y
中科院分区：
文献类型：
--
作者：
Coull, JAM;Beggs, S;De Koninck, Y
周围神经损伤后发生的神经性疼痛取决于脊髓背角神经元的过度兴奋性（1-3）。由ATP刺激的脊髓小胶质细胞导致触觉异常性疼痛，这是一种由神经损伤引起的疼痛的高度衰弱症状（4）。因此，小胶质细胞和神经元之间的信号传导是神经病理性疼痛传递的重要环节，但这种信号传导如何发生尚不清楚。在这里，我们表明，ATP刺激的小胶质细胞引起去极化移位的阴离子反转电位（E-阴离子）在脊髓板层I神经元。这种转变逆转了GABA（γ-氨基丁酸）激活的电流极性，正如已经证明的那样，发生在周围神经损伤后（5）。应用脑源性神经营养因子（BDNF）模拟Eanion的改变。阻断BDNF和受体TrkB之间的信号传导逆转了神经损伤和ATP刺激的小胶质细胞给药后的异常性疼痛和E-阴离子转移。ATP刺激诱发小胶质细胞释放BDNF。通过在ATP刺激前用针对BDNF的干扰RNA预处理小胶质细胞来防止BDNF从小胶质细胞释放，也抑制了这些细胞对退缩阈值和E-阴离子的影响。我们的研究结果表明，ATP刺激的小胶质细胞的信号板I神经元，导致其跨膜阴离子梯度的崩溃，而BDNF是一个至关重要的小胶质细胞和神经元之间的信号分子。阻断这种小胶质细胞-神经元信号传导通路可能代表治疗神经性疼痛的治疗策略。
Neuropathic pain that occurs after peripheral nerve injury depends on the hyperexcitability of neurons in the dorsal horn of the spinal cord(1-3). Spinal microglia stimulated by ATP contribute to tactile allodynia, a highly debilitating symptom of pain induced by nerve injury(4). Signalling between microglia and neurons is therefore an essential link in neuropathic pain transmission, but how this signalling occurs is unknown. Here we show that ATP-stimulated microglia cause a depolarizing shift in the anion reversal potential (E-anion) in spinal lamina I neurons. This shift inverts the polarity of currents activated by GABA (gamma-amino butyric acid), as has been shown to occur after peripheral nerve injury(5). Applying brain-derived neurotrophic factor ( BDNF) mimics the alteration in Eanion. Blocking signalling between BDNF and the receptor TrkB reverses the allodynia and the E-anion shift that follows both nerve injury and administration of ATP-stimulated microglia. ATP stimulation evokes the release of BDNF from microglia. Preventing BDNF release from microglia by pretreating them with interfering RNA directed against BDNF before ATP stimulation also inhibits the effects of these cells on the withdrawal threshold and E-anion. Our results show that ATP-stimulated microglia signal to lamina I neurons, causing a collapse of their transmembrane anion gradient, and that BDNF is a crucial signalling molecule between microglia and neurons. Blocking this microglia-neuron signalling pathway may represent a therapeutic strategy for treating neuropathic pain.