Role of mitogen-activated protein kinase activation in injured and intact primary afferent neurons for mechanical and heat hypersensitivity after spinal nerve ligation
Role of mitogen-activated protein kinase activation in injured and intact primary afferent neurons for mechanical and heat hypersensitivity after spinal nerve ligation
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DOI：
10.1523/jneurosci.3388-04.2004
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发表时间：
2004-11-10
影响因子：
5.3
通讯作者：
Noguchi, K
中科院分区：
文献类型：
--
作者：
Obata, K;Yamanaka, H;Noguchi, K
为了研究受损和/或未受损初级传入纤维中丝裂原活化蛋白激酶（MAPK）的激活是否参与部分神经损伤后的神经病理性疼痛，我们在L5脊神经结扎（SNL）模型中检测了L4和L5背根神经节（DRG）中细胞外信号调节蛋白激酶（ERK）、p38 MAPK和c-Jun N-末端激酶（JNK）的磷酸化。我们首先证实，使用激活转录因子3和神经肽Y免疫反应，几乎所有的L4 DRG神经元都幸免于轴突切断术在这个模型中。在受损的L5 DRG中，L5 SNL诱导不同群体DRG神经元中ERK、p38和JNK的激活。与此相反，在未受伤的L4 DRG，L5 SNL诱导仅p38激活酪氨酸激酶A表达的小到中等直径的神经元。鞘内注射ERK、p38和JNK抑制剂可逆转SNL诱导的机械性异常性疼痛，而仅应用p38抑制剂可减弱SNL诱导的热痛觉过敏。此外，L5背根切断术不能防止SNL诱导的热痛觉过敏。因此，我们假设未受伤的L4背根神经节中的p38激活可能参与L5 SNL模型中热过敏性的发展。事实上，p38抑制剂和抗神经生长因子的治疗减少了SNL诱导的脑源性神经营养因子和L4 DRG中瞬时受体电位香草酸1型表达的上调。总之，我们的研究结果表明，L5 SNL诱导的MAPK在受伤和未受伤的DRG神经元的差异激活，此外，MAPK激活的初级传入可能参与产生疼痛超敏反应后，部分神经损伤。
To investigate whether activation of mitogen-activated protein kinase ( MAPK) in damaged and/or undamaged primary afferents participates in neuropathic pain after partial nerve injury, we examined the phosphorylation of extracellular signal-regulated protein kinase ( ERK), p38 MAPK, and c-Jun N-terminal kinase ( JNK) in the L4 and L5 dorsal root ganglion ( DRG) in the L5 spinal nerve ligation ( SNL) model. We first confirmed, using activating transcription factor 3 and neuropeptide Y immunoreactivity, that virtually all L4 DRG neurons are spared from axotomy in this model. In the injured L5 DRG, the L5 SNL induced the activation of ERK, p38, and JNK in different populations of DRG neurons. In contrast, in the uninjured L4 DRG, the L5 SNL induced only p38 activation in tyrosine kinase A-expressing small-to medium-diameter neurons. Intrathecal ERK, p38, and JNK inhibitor infusions reversed SNL-induced mechanical allodynia, whereas only p38 inhibitor application attenuated SNL-induced thermal hyperalgesia. Furthermore, the L5 dorsal rhizotomy did not prevent SNL-induced thermal hyperalgesia. We therefore hypothesized that p38 activation in the uninjured L4 DRG might be involved in the development of heat hypersensitivity in the L5 SNL model. In fact, the treatment of the p38 inhibitor and also anti-nerve growth factor reduced SNL-induced upregulation of brain-derived neurotrophic factor and transient receptor potential vanilloid type 1 expression in the L4 DRG. Together, our results demonstrate that the L5 SNL induces differential activation of MAPK in injured and uninjured DRG neurons and, furthermore, that MAPK activation in the primary afferents may participate in generating pain hypersensitivity after partial nerve injury.