Postoperative pain is a major clinical problem imposing a significant burden on patients and society. In a survey 2 years after orthopedic surgery, 57% of patients reported persisting postoperative pain. However, only limited progress has been made in the development of safe and effective therapies to prevent the onset and chronification of pain after orthopedic surgery. We established a tibial fracture mouse model that recapitulates clinically relevant orthopedic trauma surgery, which causes changes in neuropeptide levels in dorsal root ganglia and sustained neuroinflammation in the spinal cord. Here, we monitored extended pain behavior in this model, observing chronic bilateral hindpaw mechanical allodynia in both male and female C57BL/6J mice that persisted for >3 months after surgery. We also tested the analgesic effects of a novel, minimally invasive, bioelectronic approach to percutaneously stimulate the vagus nerve (termed percutaneous vagus nerve stimulation [pVNS]). Weekly pVNS treatment for 30 minutes at 10 Hz for 3 weeks after the surgery strongly reduced pain behaviors compared with untreated controls. Percutaneous vagus nerve stimulation also improved locomotor coordination and accelerated bone healing. In the dorsal root ganglia, vagal stimulation inhibited the activation of glial fibrillary acidic protein-positive satellite cells but without affecting microglial activation. Overall, these data provide novel evidence supportive of the use of pVNS to prevent postoperative pain and inform translational studies to test antinociceptive effects of bioelectronic medicine in the clinic.

中文翻译：

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迷走神经刺激可缓解成年小鼠骨科手术后的持续疼痛。

术后疼痛是一个主要的临床问题，给患者和社会带来了沉重的负担。在骨科手术 2 年后的一项调查中，57% 的患者报告术后持续疼痛。然而，在开发安全有效的疗法来预防骨科手术后疼痛的发作和慢性化方面仅取得有限的进展。我们建立了胫骨骨折小鼠模型，该模型概括了临床相关的骨科创伤手术，该手术导致背根神经节中神经肽水平的变化和脊髓中持续的神经炎症。在这里，我们监测了该模型中的长期疼痛行为，观察了雄性和雌性 C57BL/6J 小鼠的慢性双侧后爪机械异常性疼痛，这种疼痛在手术后持续超过 3 个月。我们还测试了一种新型微创生物电子方法经皮刺激迷走神经（称为经皮迷走神经刺激 [pVNS]）的镇痛效果。与未治疗的对照相比，术后每周以 10 Hz 频率进行 30 分钟的 pVNS 治疗，持续 3 周，大大减少了疼痛行为。经皮迷走神经刺激还可以改善运动协调性并加速骨愈合。在背根神经节中，迷走神经刺激抑制胶质纤维酸性蛋白阳性卫星细胞的活化，但不影响小胶质细胞的活化。总体而言，这些数据提供了支持使用 pVNS 预防术后疼痛的新证据，并为临床测试生物电子医学的抗伤害作用的转化研究提供了信息。