AXL signaling in primary sensory neurons contributes to chronic compression of dorsal root ganglion-induced neuropathic pain in rats
AXL signaling in primary sensory neurons contributes to chronic compression of dorsal root ganglion-induced neuropathic pain in rats
复制标题
初级感觉神经元中的 AXL 信号传导导致大鼠背根神经节慢性受压引起的神经性疼痛
DOI：
10.1177/1744806919900814
复制
发表时间：
2020-01-01
期刊：
影响因子：
3.3
通讯作者：
Yuan, Chunmei
中科院分区：
文献类型：
--
作者：
Liang, Lingli;Zhang, Jun;Yuan, Chunmei
腰痛是老年人中一种慢性、高发且难以治疗的疾病。临床研究表明，属于酪氨酸激酶受体亚家族的AXL介导病理性疼痛。然而，目前还不清楚AXL是如何调节疼痛行为的。在本研究中，我们采用慢性压迫背根神经节诱导的神经性疼痛模型，重建临床椎间孔狭窄和相关腰脚痛，以探讨初级感觉神经元中的AXL是否与大鼠神经性疼痛有关。通过双标记免疫荧光，我们观察到磷酸化的AXL和AXL主要定位于分离素b4阳性和降钙素基因相关肽阳性的神经元上，而AXL也定位于神经丝200阳性的神经元上。慢性压迫背根神经节引起的疼痛与损伤背根神经节中AXL mRNA和蛋白表达上调有关。反复鞘内给药AXL抑制剂TP0903或AXL小干扰RNA可有效缓解背根神经节慢性压迫引起的疼痛超敏反应。此外，反复鞘内给药TP0903或AXL小干扰RNA均可降低哺乳动物雷帕霉素靶蛋白在损伤背根神经节中的表达，提示哺乳动物雷帕霉素靶蛋白可能介导了AXL的作用。这些结果表明，背根神经节AXL的上调可能通过细胞内雷帕霉素信号通路参与神经性疼痛的外周机制。因此，虽然目前AXL抑制剂主要在肿瘤治疗中表现出临床疗效，但AXL干预也可以作为治疗神经性疼痛的潜在靶点。
Low back pain is a chronic, highly prevalent, and hard-to-treat condition in the elderly. Clinical studies indicate that AXL, which belongs to the tyrosine kinase receptor subfamily, mediates pathological pain. However, it is not clear exactly how AXL regulates pain behaviors. In this study, we used a model of chronic compression of dorsal root ganglion-induced neuropathic pain to recreate clinical intervertebral foramen stenosis and related lumbocrural pain to explore whether AXL in primary sensory neurons contributes to this neuropathic pain in rats. Using double-labeling immunofluorescence, we observed that both phosphorylated AXL and AXL were localized primarily on isolectin B4-positive and calcitonin gene-related peptide-positive neurons, while AXL was also localized in neurofilament-200-positive neurons. Chronic compression of dorsal root ganglion-induced pain was associated with the upregulation of AXL mRNA and protein in injured dorsal root ganglia. Repeated intrathecal administration of the AXL inhibitor, TP0903, or the AXL small interfering RNA effectively alleviated chronic compression of dorsal root ganglion-induced pain hypersensitivities. Moreover, repeated intrathecal administration of either TP0903 or AXL small interfering RNA reduced the expression of mammalian target of rapamycin in injured dorsal root ganglia, suggesting that mammalian target of rapamycin may mediate AXL’s actions. These results indicate that the upregulation of dorsal root ganglion AXL may be part of a peripheral mechanism of neuropathic pain via an intracellular mammalian target of rapamycin-signaling pathway. Thus, while AXL inhibitors have so far primarily shown clinical efficacy in tumor treatment, AXL intervention could also serve as a potential target for the treatment of neuropathic pain.