A peptide c-Jun N-terminal kinase (JNK) inhibitor blocks mechanical allodynia after spinal nerve ligation: Respective roles of JNK activation in primary sensory neurons and spinal astrocytes for neuropathic pain development and maintenance
A peptide c-Jun N-terminal kinase (JNK) inhibitor blocks mechanical allodynia after spinal nerve ligation: Respective roles of JNK activation in primary sensory neurons and spinal astrocytes for neuropathic pain development and maintenance
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DOI：
10.1523/jneurosci.5290-05.2006
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发表时间：
2006-03-29
影响因子：
5.3
通讯作者：
Ji, RR
中科院分区：
文献类型：
--
作者：
Zhuang, ZY;Wen, YR;Ji, RR
神经性疼痛的最佳治疗是一项重大的临床挑战。我们研究了 c-Jun N 末端激酶 (JNK) 在脊神经结扎 (SNL) (L5) 产生的神经性疼痛中的作用。 SNL 诱导脊髓中表达 GFAP 的星形胶质细胞中 JNK（尤其是 JNK1）缓慢（> 3 d）和持续（> 21 d）激活。相比之下，SNL 后脊髓小胶质细胞中发现 p38 丝裂原激活蛋白激酶激活，到 21 天时已降至接近基础水平。鞘内输注 JNK 肽抑制剂 D-JNKI-1 不会影响正常的疼痛反应，但可以有效预防和逆转 SNL 引起的机械异常性疼痛（神经性疼痛的主要症状）。鞘内注射 D-JNKI-1 还可抑制 SNL 诱导的脊髓星形胶质细胞中 JNK 底物 c-Jun 的磷酸化。然而，脊髓 D-JNKI-1 输注并没有减弱 SNL 诱导的 GFAP 上调。此外，SNL 在 L5（受伤）而非 L4（完整）DRG 中诱导 JNK 快速（< 12 小时）但短暂的激活。 DRG 中的 JNK 激活主要存在于小型 C 纤维神经元中。将 D-JNKI-1 注入 L5 DRG 可预防但不能逆转 SNL 诱导的机械异常性疼痛。最后，鞘内注射星形胶质细胞毒素 L-α-氨基己二酸可逆转机械性异常性疼痛。我们的数据表明，DRG 和脊髓中的 JNK 激活分别在调节神经性疼痛的发展和维持中发挥着不同的作用，并且脊髓星形胶质细胞对机械性异常性疼痛的持续存在发挥着重要作用。靶向脊髓星形胶质细胞中的 JNK 通路可能会提供一种治疗神经性疼痛症状的新且有效的方法。
Optimal management of neuropathic pain is a major clinical challenge. We investigated the involvement of c-Jun N-terminal kinase (JNK) in neuropathic pain produced by spinal nerve ligation (SNL) (L5). SNL induced a slow (> 3 d) and persistent (> 21 d) activation of JNK, in particular JNK1, in GFAP-expressing astrocytes in the spinal cord. In contrast, p38 mitogen-activated protein kinase activation was found in spinal microglia after SNL, which had fallen to near basal level by 21 d. Intrathecal infusion of a JNK peptide inhibitor, D-JNKI-1, did not affect normal pain responses but potently prevented and reversed SNL-induced mechanical allodynia, a major symptom of neuropathic pain. Intrathecal D-JNKI-1 also suppressed SNL-induced phosphorylation of the JNK substrate, c-Jun, in spinal astrocytes. However, SNL-induced upregulation of GFAP was not attenuated by spinal D-JNKI-1 infusion. Furthermore, SNL induced a rapid (< 12 h) but transient activation of JNK in the L5 (injured) but not L4 (intact) DRG. JNK activation in the DRG was mainly found in small-sized C-fiber neurons. Infusion of D-JNKI-1 into the L5 DRG prevented but did not reverse SNL- induced mechanical allodynia. Finally, intrathecal administration of an astroglial toxin, L-alpha-aminoadipate, reversed mechanical allodynia. Our data suggest that JNK activation in the DRG and spinal cord play distinct roles in regulating the development and maintenance of neuropathic pain, respectively, and that spinal astrocytes contribute importantly to the persistence of mechanical allodynia. Targeting the JNK pathway in spinal astroglia may present a new and efficient way to treat neuropathic pain symptoms.