Kasai Yusuke, Aso Koji, Izumi Masashi, Wada Hiroyuki, Dan Junpei, Satake Yoshinori, Morimoto Toru, Ikeuchi Masahiko
Department of Orthopedic Surgery, Kochi Medical School, Kochi University, Nankoku, 783-8505, Japan.
J Pain Res. 2021 Nov 15;14:3565-3571. doi: 10.2147/JPR.S327457. eCollection 2021.
Nonunion bone fracture can be a cause of persistent pain, but the pathophysiology remains largely unknown. The objective of this study was to identify how nonunion affect persistent pain after fracture. Specifically, we evaluated the association of neuropeptide change in dorsal root ganglia (DRG) and nerve proliferation at fracture sites with pain.
Rat union and nonunion fracture models were created. A piece of latex glove was placed at the fracture site to create a nonunion model. At 6 weeks after surgery, bone healing was assessed using radiography. In addition, the presence of calcitonin gene-related peptide-immunoreactive (CGRP-IR) DRG at the level of L3 and anti-growth associated protein 43-immunoreactive (GAP43-IR) nerve fibers in the scar tissue between the bone fragments were evaluated. Pain-related behavior was assessed using forced treadmill running.
In radiological images at 6 weeks after surgery, callus formation was formed continuously between bone fragments in the union models. On the one hand, a clear gap was detected between fragments in nonunion models. The percentage of CGRP-IR DRG cells and the density of GAP43-IR nerve fibers in the scar tissue between the bone fragments in nonunion models was significantly higher than that in union models (p < 0.05). An increase in inflammatory cell infiltrate was observed in scar tissues in the nonunion models. During forced treadmill running, rats in the union model could run significantly longer than those in the nonunion models.
Increased CGRP expression in DRG cells and abnormal nerve proliferation secondary to prolonged inflammation could lead to persistent pain after bone fracture. In clinical practice, early achievement of bone union may minimize the development of persistent pain after fractures.
骨不连可导致持续性疼痛，但其病理生理学在很大程度上仍不清楚。本研究的目的是确定骨不连如何影响骨折后的持续性疼痛。具体而言，我们评估了背根神经节（DRG）中神经肽变化以及骨折部位神经增殖与疼痛的关联。
建立大鼠骨折愈合和骨不连模型。在骨折部位放置一块乳胶手套以创建骨不连模型。术后6周，使用X射线摄影评估骨愈合情况。此外，评估L3水平降钙素基因相关肽免疫反应性（CGRP-IR）DRG以及骨碎片间瘢痕组织中抗生长相关蛋白43免疫反应性（GAP43-IR）神经纤维的存在情况。使用强迫跑步机跑步评估疼痛相关行为。
术后6周的放射影像显示，骨折愈合模型中骨碎片间持续形成骨痂。另一方面，骨不连模型的碎片间检测到明显间隙。骨不连模型中骨碎片间瘢痕组织中CGRP-IR DRG细胞百分比和GAP43-IR神经纤维密度显著高于骨折愈合模型（p<0.05）。在骨不连模型的瘢痕组织中观察到炎性细胞浸润增加。在强迫跑步机跑步期间，骨折愈合模型中的大鼠比骨不连模型中的大鼠能跑更长时间。
DRG细胞中CGRP表达增加以及长期炎症继发的异常神经增殖可能导致骨折后持续性疼痛。在临床实践中，早期实现骨愈合可能会将骨折后持续性疼痛的发生降至最低。
