It is well‐established that spinal microglia and peripheral macrophages play critical roles in the etiology of neuropathic pain; however, growing evidence suggests sex differences in pain hypersensitivity owing to microglia and macrophages. Therefore, it is crucial to understand sex‐ and androgen‐dependent characteristics of pain‐related myeloid cells in mice with nerve injury‐induced neuropathic pain. To deplete microglia and macrophages, pexidartinib (PLX3397), an inhibitor of the colony‐stimulating factor 1 receptor, was orally administered, and mice were subjected to partial sciatic nerve ligation (PSL). Following PSL induction, healthy male and female mice and male gonadectomized (GDX) mice exhibited similar levels of spinal microglial activation, peripheral macrophage accumulation, and mechanical allodynia. Treatment with PLX3397 significantly suppressed mechanical allodynia in normal males; this was not observed in female and GDX male mice. Sex‐ and androgen‐dependent differences in the PLX3397‐mediated preventive effects were observed on spinal microglia and dorsal root ganglia (DRG) macrophages, as well as in expression patterns of pain‐related inflammatory mediators in these cells. Conversely, no sex‐ or androgen‐dependent differences were detected in sciatic nerve macrophages, and inhibition of peripheral CC‐chemokine receptor 5 prevented neuropathic pain in both sexes. Collectively, these findings demonstrate the presence of considerable sex‐ and androgen‐dependent differences in the etiology of neuropathic pain in spinal microglia and DRG macrophages but not in sciatic nerve macrophages. Given that the mechanisms of neuropathic pain may differ among experimental models and clinical conditions, accumulating several lines of evidence is crucial to comprehensively clarifying the sex‐dependent regulatory mechanisms of pain.

中文翻译：

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Pexidartinib 对神经损伤引起的小鼠神经性疼痛的性别二态性影响

众所周知，脊髓小胶质细胞和外周巨噬细胞在神经性疼痛的病因学中发挥着关键作用。然而，越来越多的证据表明，小胶质细胞和巨噬细胞导致疼痛超敏反应存在性别差异。因此，了解神经损伤引起的神经性疼痛小鼠中疼痛相关骨髓细胞的性别和雄激素依赖性特征至关重要。为了消除小胶质细胞和巨噬细胞，口服集落刺激因子 1 受体抑制剂佩西达替尼 (PLX3397)，并对小鼠进行部分坐骨神经结扎 (PSL)。 PSL 诱导后，健康雄性和雌性小鼠以及雄性去性腺 (GDX) 小鼠表现出相似水平的脊髓小胶质细胞活化、外周巨噬细胞积聚和机械异常性疼痛。 PLX3397 治疗可显着抑制正常男性的机械性异常性疼痛；在雌性和 GDX 雄性小鼠中未观察到这一现象。在脊髓小胶质细胞和背根神经节（DRG）巨噬细胞上观察到 PLX3397 介导的预防作用存在性别和雄激素依赖性差异，以及这些细胞中疼痛相关炎症介质的表达模式。相反，在坐骨神经巨噬细胞中未检测到性别或雄激素依赖性差异，并且抑制外周 CC 趋化因子受体 5 可预防两性的神经性疼痛。总的来说，这些发现表明，脊髓小胶质细胞和背节巨噬细胞的神经病理性疼痛的病因存在相当大的性别和雄激素依赖性差异，但坐骨神经巨噬细胞则不然。鉴于神经性疼痛的机制可能因实验模型和临床条件而异，积累多方面的证据对于全面阐明疼痛的性别依赖性调节机制至关重要。