Development of an in vivo mouse model of discogenic low back pain
Development of an in vivo mouse model of discogenic low back pain
复制标题
DOI：
10.1002/jcp.26280
复制
发表时间：
2018-10-01
影响因子：
5.6
通讯作者：
Im, Hee-Jeong
中科院分区：
文献类型：
--
作者：
Shi, Changgui;Das, Vaskar;Im, Hee-Jeong
椎间盘源性腰痛 (DLBP) 极为常见且费用高昂。由于 DLBP 的发病机制尚不清楚，因此缺乏有效的治疗方法。目前，尚无DLBP的体内小鼠模型，这限制了该领域的研究。本研究的目的是在小鼠中建立可靠的 DLBP 模型，捕捉椎间盘的病理变化并进行纵向疼痛测试。该模型是通过穿刺小鼠腰椎间盘（L4/5、L5/6 和 L6/S1）并在显微镜下使用显微手术刀去除髓核而生成的。对组织学、分子途径和疼痛相关行为进行了检查。术后 12 周内，动物表现出机械、热和冷痛觉过敏，同时挖洞和饲养行为减少。组织学显示进行性椎间盘退变，伴有椎间盘高度降低、髓核减少、蛋白聚糖耗竭和环状纤维化解体。免疫组织化学显示第 2 周和第 4 周炎症介质显着增加。从2周到实验结束，神经生长因子上调。 4周后，在受伤的椎间盘中诱导神经纤维向内生长。椎间盘穿刺还使背根神经节神经元中的神经肽上调，并激活脊髓背角中的神经胶质细胞。这些发现表明，椎间盘的细胞和结构变化，以及周围和中枢神经系统的可塑性，与持续且强烈的行为疼痛反应相平行。因此，该小鼠 DLBP 模型可用于研究椎间盘源性疼痛的机制，从而促进有效的药物筛选和治疗 DLBP 的开发。
Discogenic low back pain (DLBP) is extremely common and costly. Effective treatments are lacking due to DLBP's unknown pathogenesis. Currently, there are no in vivo mouse models of DLBP, which restricts research in this field. The aim of this study was to establish a reliable DLBP model in mouse that captures the pathological changes in the disc and allows longitudinal pain testing. The model was generated by puncturing the mouse lumbar discs (L4/5, L5/6, and L6/S1) and removing the nucleus pulposus using a microscalpel under the microscope. Histology, molecular pathways, and pain-related behaviors were examined. Over 12 weeks post-surgery, animals displayed the mechanical, heat, and cold hyperalgesia along with decreased burrowing and rearing. Histology showed progressive disc degeneration with loss of disc height, nucleus pulposus reduction, proteoglycan depletion, and annular fibrotic disorganization. Immunohistochemistry revealed a substantial increase in inflammatory mediators at 2 and 4 weeks. Nerve growth factor was upregulated from 2 weeks to the end of the experiment. Nerve fiber ingrowth was induced in the injured discs after 4 weeks. Disc-puncture also produced an upregulation of neuropeptides in dorsal root ganglia neurons and an activation of glial cells in the spinal cord dorsal horn. These findings indicate that the cellular and structural changes in discs, as well as peripheral and central nervous system plasticity, paralleled persistent, and robust behavioral pain responses. Therefore, this mouse DLBP model could be used to investigate mechanisms underlying discogenic pain, thereby facilitating effective drug screening and development of treatments for DLBP.