Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Rehabilitation Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.
Pain Physician. 2017 Jul;20(5):419-427.
Clinically, chronic low back pain and sciatica associated with lumbar disc herniation (LDH) is a common musculoskeletal disorder. Due to the unawareness of detailed mechanisms, it is difficult to get an effective therapy.
The aim of the present study was to identify the role of the RAGE/STAT3 pathway in the dorsal root ganglion (DRG) on the formation and development of persistent pain hypersensitivity induced by LDH.
Controlled animal study.
University laboratory.
After LDH induced by implantation of autologous nucleus pulposus (NP, harvested from animal tail) on the left L5 nerve root was established, mechanical thresholds and electrophysiological tests were conducted at relevant time points during an observation period of 28 days. Protein levels and localization of RAGE and p-STAT3 were performed by using Western blotting and immunohistochemistry, respectively.
LDH induced persistent pain hypersensitivity, increased excitability of DRG neurons, and upregulated the expression of RAGE and p-STAT3 in the DRG. Consecutive injection of both RAGE antagonist FPS-ZM1 (i.t.) and STAT3 activity inhibitor S3I-201 (i.t.) inhibited the enhanced excitability of DRG neurons and mechanical allodynia induced by NP implantation. Furthermore, local knockdown of STAT3 by intrathecal injection of AAV-Cre-GFP into STAT3flox/flox mice markedly alleviated NP implantation-induced mechanical allodynia in mice. Importantly, the expression of p-STAT3 was colocalized with that of RAGE in the DRG and inhibition of RAGE with FPS-ZM1 prevented NP implantation-induced STAT3 activation.
More underlying mechanism(s) of the role of the RAGE/STAT3 pathway on the formation and development of persistent pain hypersensitivity induced by LDH will be needed to be explored in future research.
These findings suggest activation of the RAGE/STAT3 pathway plays a critical role in persistent pain induced by LDH, and this pathway may represent novel therapeutic targets for the treatment of LDH-induced persistent pain.
Lumbar disc herniation, persistent pain, RAGE, STAT3, DRG.
临床上，与腰椎间盘突出症（LDH）相关的慢性下腰痛和坐骨神经痛是一种常见的肌肉骨骼疾病。由于对详细机制缺乏认识，因此很难进行有效的治疗。
本研究旨在确定 RAGE/STAT3 通路在背根神经节（DRG）中在 LDH 引起的持续性疼痛敏化形成和发展中的作用。
对照动物研究。
大学实验室。
在左侧 L5 神经根上植入自体髓核（NP，取自动物尾巴）诱导 LDH 后，在 28 天的观察期内的相关时间点进行机械阈值和电生理测试。通过 Western blot 和免疫组织化学分别检测 RAGE 和 p-STAT3 的蛋白水平和定位。
LDH 诱导持续性疼痛敏化，增加 DRG 神经元的兴奋性，并上调 DRG 中 RAGE 和 p-STAT3 的表达。连续注射 RAGE 拮抗剂 FPS-ZM1（鞘内）和 STAT3 活性抑制剂 S3I-201（鞘内）抑制 NP 植入引起的 DRG 神经元兴奋性增强和机械性痛觉过敏。此外，STAT3flox/flox 小鼠鞘内注射 AAV-Cre-GFP 进行 STAT3 敲低显着减轻了 NP 植入引起的小鼠机械性痛觉过敏。重要的是，DRG 中 p-STAT3 与 RAGE 的表达共定位，用 FPS-ZM1 抑制 RAGE 可防止 NP 植入诱导的 STAT3 激活。
未来的研究需要探索 RAGE/STAT3 通路在 LDH 引起的持续性疼痛敏化形成和发展中的作用的更多潜在机制。
这些发现表明，RAGE/STAT3 通路的激活在 LDH 引起的持续性疼痛中起关键作用，该通路可能代表治疗 LDH 引起的持续性疼痛的新治疗靶点。
腰椎间盘突出症，持续性疼痛，RAGE，STAT3，DRG。
