Activation of Src-family kinases in spinal microglia contributes to mechanical hypersensitivity after nerve injury
Activation of Src-family kinases in spinal microglia contributes to mechanical hypersensitivity after nerve injury
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DOI：
10.1523/jneurosci.1771-06.2006
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发表时间：
2006-08-23
影响因子：
5.3
通讯作者：
Noguchi, Koichi
中科院分区：
文献类型：
--
作者：
Katsura, Hirokazu;Obata, Koichi;Noguchi, Koichi
对机械刺激的过敏是神经性疼痛的一个有据可查的症状，目前尚无有效的治疗方法。 Src 家族激酶 (SFK) 参与增殖和分化以及神经元可塑性，包括长时程增强、学习和记忆。在这里，我们表明脊髓小胶质细胞中诱导的 SFK 激活对于周围神经损伤后的机械超敏反应至关重要。神经损伤导致同侧背角 SFK 磷酸化显着增加，并且 SFK 在过度活跃的小胶质细胞中被激活，但在神经元或星形胶质细胞中则未被激活。鞘内注射 Src 家族酪氨酸激酶抑制剂 4-氨基-5-(4-氯苯基)-7-(叔丁基)吡唑并[3,4-d]嘧啶 (PP2) 可抑制神经损伤引起的机械超敏反应，但不能抑制热和冷超敏反应。此外，PP2 可以逆转脊髓小胶质细胞中细胞外信号调节蛋白激酶 (ERK) 的激活，但不能逆转 p38 丝裂原激活蛋白激酶的激活。相反，初级感觉神经元中SFK磷酸化没有变化，PP2没有降低感觉神经元中瞬时受体电位离子通道TRPV1和TRPA1的诱导。总之，这些结果表明脊髓小胶质细胞中的 SFK 激活有助于通过 ERK 途径产生机械超敏反应。因此，阻止小胶质细胞中 Src/ERK 信号级联的激活可能为治疗神经性疼痛提供有效的策略。
Hypersensitivity to mechanical stimulation is a well documented symptom of neuropathic pain, for which there is currently no effective therapy. Src-family kinases (SFKs) are involved in proliferation and differentiation and in neuronal plasticity, including long-term potentiation, learning, and memory. Here we show that activation of SFKs induced in spinal cord microglia is crucial for mechanical hypersensitivity after peripheral nerve injury. Nerve injury induced a striking increase in SFK phosphorylation in the ipsilateral dorsal horn, and SFKs were activated in hyperactive microglia but not in neurons or astrocytes. Intrathecal administration of the Src-family tyrosine kinase inhibitor 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2) suppressed nerve injury-induced mechanical hypersensitivity but not heat and cold hypersensitivity. Furthermore, PP2 reversed the activation of extracellular signal-regulated protein kinase (ERK), but not p38 mitogen-activated protein kinase, in spinal microglia. In contrast, there was no change in SFK phosphorylation in primary sensory neurons, and PP2 did not decrease the induction of transient receptor potential ion channel TRPV1 and TRPA1 in sensory neurons. Together, these results demonstrate that SFK activation in spinal microglia contributes to the development of mechanical hypersensitivity through the ERK pathway. Therefore, preventing the activation of the Src/ERK signaling cascade in microglia might provide a fruitful strategy for treating neuropathic pain.