Department of Anesthesiology, Kyoto Prefectural University of Medicine, Kajii-cho 465, Kyoto 6028566, Japan; Research Unit for the Neurobiology of Pain, Department of Anesthesiology, Kyoto Prefectural University of Medicine, Kajii-cho 465, Kyoto 6028566, Japan.
United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu, Japan; Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, Gifu, Japan.
Neuroscience. 2018 Dec 1;394:288-299. doi: 10.1016/j.neuroscience.2018.08.005.
Little is known about the functional relationship between endoplasmic reticulum (ER) stress and development of pain hypersensitivity after nerve injury. The aim of this study was to investigate the role of ER stress in the development of pain hypersensitivity in the dorsal root ganglion (DRG) after spinal nerve ligation (SNL). SNL was performed in male Sprague-Dawley rats. Real-time PCR and immunohistochemistry were performed to investigate ER stress markers including glucose-regulated protein (GRP) 78, C/EBP homologous protein (CHOP), and spliced form of the X-box binding protein 1 (sXBP1) in L4 and L5 DRG. Behavioral assessment with von Frey filaments, radiant heat, and acetone stimulation was performed to investigate pain hypersensitivity. The ER stress inhibitor salubrinal was administered prior to and 1, 3, and 5 days after SNL treatment. Separately, the ER stress inducer tunicamycin was applied to L5 DRG. GRP78, CHOP, and sXBP1 mRNA and protein expression in L5 DRG was increased 1 and 3 days after SNL but returned to baseline 7 days after SNL. In L4 DRG, ER stress markers showed no remarkable change. Immunohistochemistry demonstrated that GRP78 expression was detected in the majority of DRG neurons and in satellite glial cells. Treatment with salubrinal inhibited CHOP expression in L5 DRG and alleviated pain hypersensitivity for 5 days after SNL. Tunicamycin induced ER stress in the DRG and pain hypersensitivity 2 h after treatment. These results demonstrated that ER stress is induced in the injured DRG and contributes to the development of pain hypersensitivity after nerve injury.
关于内质网应激(endoplasmic reticulum stress, ER 应激)与神经损伤后痛觉过敏发展之间的功能关系知之甚少。本研究旨在探讨 ER 应激在脊神经结扎(spinal nerve ligation, SNL)后背根神经节(dorsal root ganglion, DRG)痛觉过敏发展中的作用。雄性 Sprague-Dawley 大鼠进行 SNL。实时 PCR 和免疫组织化学用于研究包括葡萄糖调节蛋白(glucose-regulated protein, GRP)78、C/EBP 同源蛋白(C/EBP homologous protein, CHOP)和 X 盒结合蛋白 1 的剪接形式(spliced form of the X-box binding protein 1, sXBP1)在内的 ER 应激标志物在 L4 和 L5 DRG 中的表达。使用 von Frey 细丝、辐射热和丙酮刺激进行行为评估，以研究痛觉过敏。在 SNL 治疗前和治疗后 1、3 和 5 天给予 ER 应激抑制剂 salubrinal。另外，将 ER 应激诱导剂衣霉素应用于 L5 DRG。SNL 后 1 和 3 天，L5 DRG 中 GRP78、CHOP 和 sXBP1 mRNA 和蛋白表达增加，但在 SNL 后 7 天恢复基线。在 L4 DRG 中，ER 应激标志物无明显变化。免疫组织化学显示 GRP78 表达存在于大多数 DRG 神经元和卫星胶质细胞中。Salubrinal 治疗抑制 L5 DRG 中 CHOP 表达，并在 SNL 后 5 天缓解痛觉过敏。衣霉素诱导 DRG 中的 ER 应激，并在治疗后 2 小时引起痛觉过敏。这些结果表明，ER 应激在内伤性 DRG 中被诱导，并有助于神经损伤后痛觉过敏的发展。
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