Neuronal NR2B-containing NMDA receptor mediates spinal astrocytic c-Jun N-terminal kinase activation in a rat model of neuropathic pain
Neuronal NR2B-containing NMDA receptor mediates spinal astrocytic c-Jun N-terminal kinase activation in a rat model of neuropathic pain
复制标题
神经病理性疼痛大鼠模型中含有 NR2B 的 NMDA 受体介导脊髓星形细胞 c-Jun N 末端激酶激活
DOI：
10.1016/j.bbi.2011.04.002
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发表时间：
2011-10-01
影响因子：
15.1
通讯作者：
Li, Yun-Qing
中科院分区：
文献类型：
--
作者：
Wang, Wei;Mei, Xiao-Peng;Li, Yun-Qing
脊髓N-甲基-D-天冬氨酸受体(NMDAR)在神经损伤诱导的中枢敏化中起着关键作用。最近的研究表明，NMDAR也参与了神经元-星形胶质细胞的信号传递。神经损伤后脊髓星形胶质细胞持续、特异地激活c-jun氨基末端激酶(JNK)，被认为是痛相关星形胶质细胞激活的可靠指标。NMDAR介导的脊髓背角JNK激活可能是神经病理性疼痛中神经元-星形胶质细胞信号转导的重要形式。在本研究中，我们观察到鞘内注射非竞争性NMDA受体拮抗剂MK-801或选择性拮抗含NR2B的NMDAR的Ro25-6981和ifenprodil均显著降低神经损伤诱导的JNK激活。双重免疫染色显示NR2B在神经元中高表达，提示NMDAR拮抗剂对JNK活性的影响是间接的。我们进一步观察到，鞘内注射NMDA(每天两次，连续3天)显著增加了脊髓JNK的磷酸化。此外，神经元型一氧化氮合酶(NNOS)选择性抑制剂(7-硝基吲唑钠盐)可以阻断与nmdar相关的jnk的激活，但nnos敏感的鸟酰环化酶抑制剂(1H-[1，2，4]oxadiazolo[4，3-alquinoxalin-1-one).不能阻止这种激活。实时定量RT-PCR和免疫染色显示神经损伤诱导的IL-1β的表达依赖于星形胶质细胞JNK的激活。针对NMDAR-nNOS通路的治疗也影响了IL-1β的表达，这进一步证实了我们的假设。综上所述，我们的结果提示神经元NMDAR-nNOS通路可以激活星形胶质细胞的JNK通路。兴奋性神经元传递通过这种方式启动星形胶质细胞激活引起的神经炎症，从而导致神经损伤引起的神经病理性疼痛。(C)2011 Elsevier Inc.保留所有权利。
Spinal N-methyl D-aspartate receptor (NMDAR) plays a pivotal role in nerve injury-induced central sensitization. Recent studies suggest that NMDAR also contributes to neuron-astrocyte signaling. c-Jun N-terminal kinase JNK) is persistently and specifically activated (indicated by phosphorylation) in spinal cord astrocytes after nerve injury and thus it is considered as a dependable indicator of pain-related astrocytic activation. NMDAR-mediated JNK activation in spinal dorsal horn might be an important form of neuron-astrocyte signaling in neuropathic pain. In the present study, we observed that intrathecal injection of MK-801, a noncompetitive NMDA receptor antagonist, or Ro25-6981 and ifenprodil, which are selective antagonists of NR2B-containing NMDAR each significantly reduced nerve injury-induced JNK activation. Double immunostaining showed that NR2B was highly expressed in neurons, indicating the effect of NMDAR antagonists on JNK activation was indirect. We further observed that intrathecal injection of NMDA (twice a day for 3 days) significantly increased spinal JNK phosphorylation. Besides, NMDAR-related JNK activation could be blocked by a neuronal nitric oxide synthase (nNOS) selective inhibitor (7-nitroindazole sodium salt) but not by a nNOS sensitive guanylyl cyclase inhibitor (1H-[1,2,4]oxadiazolo[4,3-alquinoxalin-1-one). Finally, real-time RT-PCR and immunostaining showed that nerve injury-induced interleukin-1beta expression was dependent on astrocytic JNK activation. Treatments targeting NMDAR-nNOS pathway also influenced interleukin-1beta expression, which further confirmed our hypothesis. Taken together, our results suggest that neuronal NMDAR-nNOS pathway could activate astrocytic JNK pathway. Excitatory neuronal transmission initiates astrocytic activation-induced neuroinflammation in this way, which contributes to nerve injury-induced neuropathic pain. (C) 2011 Elsevier Inc. All rights reserved.