The peripheral inflammatory response is an attractive therapeutic target for pain treatment. Neutrophils are the first circulating inflammatory cells recruited to sites of injury, but their contribution to pain outcomes is unclear. We performed a systematic review and meta-analysis of original preclinical studies, which evaluated the effect of preemptive neutrophil depletion on pain outcomes (PROSPERO registration number: CRD42022364004). Literature search (PubMed, January 19, 2023) identified 49 articles, which were meta-analyzed using a random-effects model. The risk of bias was evaluated using SYRCLE's tool. The pooled effect considering all studies showed that neutrophil depletion induced a consistent pain reduction. Inflammatory, joint, neuropathic, and visceral pain showed significant pain alleviation by neutrophil depletion with medium-large effect sizes. However, muscle and postoperative pain were not significantly alleviated by neutrophil depletion. Further analysis showed a differential contribution of neutrophils to pain outcomes. Neutrophils had a higher impact on mechanical hyperalgesia, followed by nociceptive behaviors and mechanical allodynia, with a smaller contribution to thermal hyperalgesia. Interspecies (mice or rats) differences were not appreciated. Analyses regarding intervention unveiled a lower pain reduction for some commonly used methods for neutrophil depletion, such as injection of antineutrophil serum or an anti-Gr-1 antibody, than for other agents such as administration of an anti-Ly6G antibody, fucoidan, vinblastine, CXCR1/2 inhibitors, and etanercept. In conclusion, the contribution of neutrophils to pain depends on pain etiology (experimental model), pain outcome, and the neutrophil depletion strategy. Further research is needed to improve our understanding on the mechanisms of these differences.

中文翻译：

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中性粒细胞在疼痛中的作用：动物研究的系统评价和荟萃分析。


外周炎症反应是疼痛治疗的有吸引力的治疗靶点。中性粒细胞是第一个被募集到损伤部位的循环炎症细胞，但它们对疼痛结果的贡献尚不清楚。我们对原始临床前研究进行了系统评价和荟萃分析，这些研究评估了抢先性中性粒细胞耗竭对疼痛结局的影响 （PROSPERO 注册号：CRD42022364004）。文献检索（PubMed，2023 年 1 月 19 日）确定了 49 篇文章，这些文章使用随机效应模型进行了荟萃分析。使用 SYRCLE 的工具评估偏倚风险。考虑所有研究的汇总效应表明，中性粒细胞耗竭诱导了一致的疼痛减轻。炎症、关节、神经性和内脏疼痛显示中性粒细胞耗竭可显着减轻疼痛，效应量为中大。然而，中性粒细胞耗竭并未显著缓解肌肉和术后疼痛。进一步分析显示中性粒细胞对疼痛结局的贡献不同。中性粒细胞对机械性痛觉过敏的影响较高，其次是伤害感受行为和机械性异常性疼痛，对热痛觉过敏的贡献较小。种间 （小鼠或大鼠） 差异未得到重视。关于干预的分析显示，一些常用的中性粒细胞耗竭方法（例如注射抗中性粒细胞血清或抗 Gr-1 抗体）的疼痛减轻程度低于其他药物（例如施用抗 Ly6G 抗体、岩藻多糖、长春碱、CXCR1/2 抑制剂和依那西普）。总之，中性粒细胞对疼痛的贡献取决于疼痛病因 （实验模型） 、疼痛结局和中性粒细胞耗竭策略。 需要进一步的研究来提高我们对这些差异机制的理解。