Obata Koichi, Yamanaka Hiroki, Kobayashi Kimiko, Dai Yi, Mizushima Toshiyuki, Katsura Hirokazu, Fukuoka Tetsuo, Tokunaga Atsushi, Noguchi Koichi
Department of Anatomy and Neuroscience, Hyogo College of Medicine, Hyogo 663-8501, Japan.
J Neurosci. 2004 Nov 10;24(45):10211-22. doi: 10.1523/JNEUROSCI.3388-04.2004.
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.
为了研究丝裂原活化蛋白激酶（MAPK）在受损和/或未受损的初级传入神经纤维中的激活是否参与部分神经损伤后的神经性疼痛，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氨基末端激酶（JNK）的磷酸化情况。我们首先使用激活转录因子3和神经肽Y免疫反应性证实，在该模型中几乎所有L4 DRG神经元都未受到轴突切断的影响。在受损的L5 DRG中，L5 SNL诱导了不同群体DRG神经元中ERK、p38和JNK的激活。相比之下，在未受损的L4 DRG中，L5 SNL仅在表达酪氨酸激酶A的中小直径神经元中诱导了p38的激活。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抑制剂可减轻SNL诱导的热痛觉过敏。此外，L5背根切断术并不能预防SNL诱导的热痛觉过敏。因此，我们推测未受损的L4 DRG中p38的激活可能参与了L5 SNL模型中热超敏反应的发生。事实上，p38抑制剂以及抗神经生长因子的治疗可降低SNL诱导的L4 DRG中脑源性神经营养因子和瞬时受体电位香草酸亚型1表达的上调。总之，我们的结果表明，L5 SNL在受损和未受损的DRG神经元中诱导了MAPK的差异激活，此外，初级传入神经纤维中的MAPK激活可能参与了部分神经损伤后疼痛超敏反应的产生。
