Center for Basic Medical Research, Medical School of Nantong University, Nantong, Jiangsu Province, 226001, China; Department of Anesthesiology, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, 226001, China.
Key Laboratory of Neuroregeneration of Jiangsu and the Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu Province, 226001, China.
Neuropharmacology. 2022 Jan 1;202:108835. doi: 10.1016/j.neuropharm.2021.108835. Epub 2021 Oct 11.
Peripheral nerve injuries (PNIs) often result in persistent neuropathic pain, seriously affecting quality of life. Existing therapeutic interventions for PNI-induced neuropathic pain are far from satisfactory. Extracellular signal-regulated kinases (ERKs) and p38 have been found to participate in triggering and maintaining PNI-induced neuropathic pain. However, ERK and p38 also contribute to axonal regeneration and motor function recovery after PNI, making it difficult to inhibit ERK and p38 for therapeutic purposes. In this study, we simultaneously characterized neuropathic pain and motor function recovery in a mouse sciatic nerve crush injury model to identify the time window for therapeutic interventions. We further demonstrated that delayed delivery of a combination of ERK and p38 inhibitors at three weeks after PNI could significantly alleviate PNI-induced neuropathic pain without affecting motor function recovery. Additionally, the combined use of these two inhibitors could suppress pain markedly better than either inhibitor alone, possibly reducing the required dose of each inhibitor and alleviating the side effects and risks of the inhibitors when used individually.
周围神经损伤 (PNI) 常导致持续性神经病理性疼痛，严重影响生活质量。现有的 PNI 诱导性神经病理性疼痛治疗干预措施远不能令人满意。现已发现细胞外信号调节激酶 (ERK) 和 p38 参与触发和维持 PNI 诱导性神经病理性疼痛。然而，ERK 和 p38 也有助于 PNI 后轴突再生和运动功能恢复，因此难以抑制 ERK 和 p38 进行治疗。在这项研究中，我们同时在小鼠坐骨神经挤压损伤模型中对神经病理性疼痛和运动功能恢复进行了特征描述，以确定治疗干预的时间窗口。我们进一步证明，在 PNI 后 3 周延迟给予 ERK 和 p38 抑制剂联合治疗，可以显著缓解 PNI 诱导性神经病理性疼痛，而不影响运动功能恢复。此外，这两种抑制剂的联合使用可以显著更好地抑制疼痛，可能减少每种抑制剂所需的剂量，并减轻单独使用时抑制剂的副作用和风险。
