Phenotypic change in trigeminal ganglion neurons associated with satellite cell activation via extracellular signal-regulated kinase phosphorylation is involved in lingual neuropathic pain
Phenotypic change in trigeminal ganglion neurons associated with satellite cell activation via extracellular signal-regulated kinase phosphorylation is involved in lingual neuropathic pain
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DOI：
10.1111/ejn.13667
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发表时间：
2017-09-01
影响因子：
3.4
通讯作者：
Iwata, Koichi
中科院分区：
文献类型：
--
作者：
Mikuzuki, Lou;Saito, Hiroto;Iwata, Koichi
医源性三叉神经损伤是临床常见而复杂的问题。已知卫星胶质细胞（SGC）活化、细胞外信号调节激酶（ERK）的相关磷酸化以及三叉神经节（TG）中神经肽的表达参与与三叉神经损伤相关的三叉神经病理性疼痛。然而，这些分子参与口面神经性疼痛机制仍然是未知的。舌神经夹伤（LNC）大鼠舌下神经节细胞ERK 1/2磷酸化。为探讨神经元-SGC相互作用在神经病理性疼痛中的作用，本研究观察了LNC大鼠三叉神经节降钙素基因相关肽（CGRP）免疫反应（IR）、磷酸化ERK 1/2（pERK 1/2）免疫反应（IR）和胶质细胞酸性蛋白（GFAP）免疫反应（IR）细胞。LNC组CGRP免疫阳性神经元和pERK 1/2免疫阳性SGCs包围的神经元数量明显多于Sham组。LNC大鼠大颗粒CGRP免疫阳性神经元的比例明显增高。CGRP受体阻断剂CGRP（8-37）或丝裂原活化蛋白激酶/ERK激酶1抑制剂PD 98059可使LNC后TG内CGRP阳性神经元、pERK 1/2阳性神经元和GFAP阳性神经元数量减少。LNC大鼠对舌的机械和热刺激的降低的阈值在CGRP（8-37）或PD 98059施用后也显著恢复。本研究结果表明，CGRP从TG神经元释放激活SGCs通过ERK 1/2磷酸化和TG神经元活性增强，导致舌神经损伤相关的舌过敏。表达CGRP的大的有髓鞘TG神经元的表型转换可能解释舌神经病理性疼痛的发病机制。
Iatrogenic trigeminal nerve injuries remain a common and complex clinical problem. Satellite glial cell (SGC) activation, associated phosphorylation of extracellular signal-regulated kinase (ERK), and neuropeptide expression in the trigeminal ganglion (TG) are known to be involved in trigeminal neuropathic pain related to trigeminal nerve injury. However, the involvement of these molecules in orofacial neuropathic pain mechanisms is still unknown. Phosphorylation of ERK1/2 in lingual nerve crush (LNC) rats was observed in SGCs. To evaluate the role of neuron-SGC interactions under neuropathic pain, calcitonin gene-related peptide (CGRP)-immunoreactive (IR), phosphorylated ERK1/2 (pERK1/2)-IR and glial fibrillary acidic protein (GFAP)-IR cells in the TG were studied in LNC rats. The number of CGRP-IR neurons and neurons encircled with pERK1/2-IR SGCs was significantly larger in LNC rats compared with sham rats. The percentage of large-sized CGRP-IR neurons was significantly higher in LNC rats. The number of CGRP-IR neurons, neurons encircled with pERK1/2-IR SGCs, and neurons encircled with GFAP-IR SGCs was decreased following CGRP receptor blocker CGRP(8-37) or mitogen-activated protein kinase/ERK kinase 1 inhibitor PD98059 administration into the TG after LNC. Reduced thresholds to mechanical and heat stimulation to the tongue in LNC rats were also significantly recovered following CGRP(8-37) or PD98059 administration. The present findings suggest that CGRP released from TG neurons activates SGCs through ERK1/2 phosphorylation and TG neuronal activity is enhanced, resulting in the tongue hypersensitivity associated with lingual nerve injury. The phenotypic switching of large myelinated TG neurons expressing CGRP may account for the pathogenesis of tongue neuropathic pain.