Differential activation of MAPK in injured and uninjured DRG neurons following chronic constriction injury of the sciatic nerve in rats
Differential activation of MAPK in injured and uninjured DRG neurons following chronic constriction injury of the sciatic nerve in rats
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DOI：
10.1111/j.1460-9568.2004.03754.x
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发表时间：
2004-12-01
影响因子：
3.4
通讯作者：
Noguchi, K
中科院分区：
文献类型：
--
作者：
Obata, K;Yamanaka, H;Noguchi, K
为探讨部分神经损伤后神经病理性疼痛的细胞内信号转导机制，我们在慢性压迫性损伤（CCI）模型中检测了背根神经节（DRG）细胞外信号调节蛋白激酶（ERK）和p38丝裂原活化蛋白激酶（MAPK）的活化。CCI诱导主要受损的中型和大型DRG神经元和卫星神经胶质细胞中ERK磷酸化的增加。用MAPK激酶1/2抑制剂U 0126治疗，抑制CCI诱导的机械异常性疼痛，并部分逆转受损DRG神经元中神经肽Y（NPY）表达的增加。与此相反，CCI诱导激活的p38，主要是在未受伤的小到中等直径的DRG神经元和卫星胶质细胞。p38抑制剂SB 203580可逆转CCI诱导的热痛觉过敏，并可逆转完整DRG神经元中脑源性神经营养因子（BDNF）表达的增加。另一方面，神经生长因子（NGF）诱导的BDNF表达增加在小到中等直径的神经元被SB 203580逆转，而抗NGF诱导的增加在中型和大型神经元中的NPY被U 0126部分阻断。两者合计，我们的研究结果表明，ERK和p38的激活，以及NPY和BDNF表达的变化可能会发生在不同群体的DRG神经元CCI后，部分通过改变靶源性NGF。损伤和完整的初级传入神经的这些变化可能在病理状态中起重要作用，伤害感受器中的MAPK通路可能是开发新型镇痛药的潜在靶点。
To investigate the intracellular signal transduction pathways involved in the pathophysiological mechanisms of neuropathic pain after partial nerve injury, we examined the activation of extracellular signal-regulated protein kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) in the dorsal root ganglion (DRG) in the chronic constriction injury (CCI) model. The CCI induced an increase in the phosphorylation of ERK in predominantly injured medium-sized and large-sized DRG neurons and in satellite glial cells. Treatment with the MAPK kinase 1/2 inhibitor, U0126, suppressed CCI-induced mechanical allodynia and partially reversed the increase in neuropeptide Y (NPY) expression in damaged DRG neurons. In contrast, the CCI induced the activation of p38, mainly in uninjured small-to-medium-diameter DRG neurons and in satellite glial cells. The p38 inhibitor, SB203580, reversed the CCI-induced heat hyperalgesia and also the increase in brain-derived neurotrophic factor (BDNF) expression in intact DRG neurons. On the other hand, the nerve growth factor (NGF)-induced increase in BDNF expression in small-to-medium-diameter neurons was reversed by SB203580, whereas the anti-NGF-induced increase in NPY in medium-sized and large-sized neurons was partially blocked by U0126. Taken together, our results demonstrate that the activation of ERK and p38 and also the changes in NPY and BDNF expression may occur in different populations of DRG neurons after CCI, partially through alterations in the target-derived NGF. These changes in injured and intact primary afferents are likely to have a substantial role in pathological states, and MAPK pathways in nociceptors may be potential targets for the development of novel analgesics.