Zhu Hong-Yan, Liu Xuelian, Miao Xiuhua, Li Di, Wang Shusheng, Xu Guang-Yin
1 Center for Translation Medicine, The Affiliated Zhangjiagang Hospital of Soochow University, Zhangjiagang, P.R. China.
2 Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Institute of Neuroscience, Soochow University, Suzhou, P.R. China.
Mol Pain. 2017 Jan;13:1744806917697979. doi: 10.1177/1744806917697979.
Background Pain in patients with chronic pancreatitis is critical hallmark that accompanied inflammation, fibrosis, and destruction of glandular pancreas. Many researchers have demonstrated that stromal cell-derived factor 1 (also named as CXCL12) and its cognate receptor C-X-C chemokine receptor type 4 (CXCR4) involved in mediating neuropathic and bone cancer pain. However, their roles in chronic pancreatic pain remain largely unclear. Methods Chronic pancreatitis was induced by intraductal injection of trinitrobenzene sulfonic acid to the pancreas. Von Frey filament tests were conducted to evaluate pancreas hypersensitivity of rat. Expression of CXCL12, CXCR4, NaV1.8, and pERK in rat dorsal root ganglion was detected by Western blot analyses. Dorsal root ganglion neuronal excitability was assessed by electrophysiological recordings. Results We showed that both CXCL12 and CXCR4 were dramatically up-regulated in the dorsal root ganglion in trinitrobenzene sulfonic acid-induced chronic pancreatitis pain model. Intrathecal application with AMD3100, a potent and selective CXCR4 inhibitor, reversed the hyperexcitability of dorsal root ganglion neurons innervating the pancreas of rats following trinitrobenzene sulfonic acid injection. Furthermore, trinitrobenzene sulfonic acid-induced extracellular signal-regulated kinase activation and Nav1.8 up-regulation in dorsal root ganglias were reversed by intrathecal application with AMD3100 as well as by blockade of extracellular signal-regulated kinase activation by intrathecal U0126. More importantly, the trinitrobenzene sulfonic acid-induced persistent pain was significantly suppressed by CXCR4 and extracellular signal-regulated kinase inhibitors. Conclusions The present results suggest that the activation of CXCL12-CXCR4 signaling might contribute to pancreatic pain and that extracellular signal-regulated kinase-dependent Nav1.8 up-regulation might lead to hyperexcitability of the primary nociceptor neurons in rats with chronic pancreatitis.
慢性胰腺炎患者的疼痛是伴随着胰腺炎症、纤维化和腺泡破坏的关键特征。许多研究人员已证明，基质细胞衍生因子1（也称为CXCL12）及其同源受体C-X-C趋化因子受体4（CXCR4）参与介导神经性疼痛和骨癌疼痛。然而，它们在慢性胰腺疼痛中的作用仍不清楚。方法：通过向胰腺内注射三硝基苯磺酸诱导慢性胰腺炎。采用von Frey细丝试验评估大鼠胰腺超敏反应。通过蛋白质印迹分析检测大鼠背根神经节中CXCL12、CXCR4、NaV1.8和pERK的表达。通过电生理记录评估背根神经节神经元兴奋性。结果：我们发现，在三硝基苯磺酸诱导的慢性胰腺炎疼痛模型中，背根神经节中的CXCL12和CXCR4均显著上调。鞘内应用强效选择性CXCR4抑制剂AMD3100可逆转三硝基苯磺酸注射后支配大鼠胰腺的背根神经节神经元的过度兴奋性。此外，鞘内应用AMD3100以及鞘内应用U0126阻断细胞外信号调节激酶激活，均可逆转三硝基苯磺酸诱导的背根神经节中细胞外信号调节激酶激活和Nav1.8上调。更重要的是，CXCR4和细胞外信号调节激酶抑制剂可显著抑制三硝基苯磺酸诱导的持续性疼痛。结论：目前的结果表明，CXCL12-CXCR4信号通路的激活可能导致胰腺疼痛，细胞外信号调节激酶依赖性Nav1.8上调可能导致慢性胰腺炎大鼠初级伤害感受神经元的过度兴奋性。
