Transforming growth factor-activated kinase 1 induced in spinal astrocytes contributes to mechanical hypersensitivity after nerve injury
Transforming growth factor-activated kinase 1 induced in spinal astrocytes contributes to mechanical hypersensitivity after nerve injury
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DOI：
10.1002/glia.20648
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发表时间：
2008-05-01
期刊：
影响因子：
6.2
通讯作者：
Noguchi, Koichi
中科院分区：
文献类型：
--
作者：
Katsura, Hirokazu;Obata, Koichi;Noguchi, Koichi
丝裂原活化蛋白激酶（MAPK）在神经病理性疼痛的诱导和维持中起重要作用。转化生长因子激活激酶I（Transforming growth factor-activated kinase I，TAK 1）是MAPK激酶家族的成员，是c-Jun N-末端激酶（JNK）和p38 MAPK激活所必需的。我们现在表明，在脊髓星形胶质细胞中诱导的TAK 1对周围神经损伤后的机械超敏性至关重要。神经损伤诱导同侧背角中TEK 1的表达显着增加，并且过度活跃的星形胶质细胞中TEK 1的表达增加，但神经元或小胶质细胞中则没有增加。鞘内注射TAK 1反义寡核苷酸（AS-ODN）可预防和逆转神经损伤诱导的机械过敏，但不能逆转热过敏。此外，TAK 1 AS-ODN抑制脊髓星形胶质细胞中JNK 1的活化，但不抑制p38 MAPK。相反，初级感觉神经元中TAK 1的表达没有变化，并且TAK 1 AS-ODN没有减弱感觉神经元中瞬时受体电位离子通道TRPV 1的诱导。总之，这些结果表明，在脊髓星形胶质细胞中的TAK 1上调具有实质性的作用，通过JNK 1通路的机械超敏反应的发展和维持。因此，阻止星形胶质细胞中的TAK 1/JNK 1信号级联反应可能为治疗顽固性神经病理性疼痛提供富有成效的策略。(c)2008 Wiley-Liss，Inc.
Mitogen-activated protein kinase (MAPK) plays an important role in the induction and maintenance of neuropathic pain. Transforming growth factor-activated kinase I (TAK1), a member of the MAPK kinase kinase family, is indispensable for the activation of c-Jun N-terminal kinase (JNK) and p38 MAPK. We now show that TAK1 induced in spinal cord astrocytes is crucial for mechanical hypersensitivity after peripheral nerve injury. Nerve injury induced a striking increase in the expression of TAK1 in the ipsilateral dorsal horn, and TAK1 was increased in hyperactive astrocytes, but not in neurons or microglia. Intrathecal administration of TAK1 antisense oligodeoxynucleotide (AS-ODN) prevented and reversed nerve injury-induced mechanical, but not heat hypersensitivity. Furthermore, TAK1 AS-ODN suppressed the activation of JNK1, but not p38 MAPK, in spinal astrocytes. In contrast, there was no change in TAK1 expression in primary sensory neurons, and TAK1 AS-ODN did not attenuate the induction of transient receptor potential ion channel TRPV1 in sensory neurons. Taken together, these results demonstrate that TAK1 upregulation in spinal astrocytes has a substantial role in the development and maintenance of mechanical hypersensitivity through the JNK1 pathway. Thus, preventing the TAK1/JNK1 signaling cascade in astrocytes might provide a fruitful strategy for treating intractable neuropathic pain. (c) 2008 Wiley-Liss, Inc.