紫杉醇 (PTX) 广泛用于治疗多种实体瘤，经常导致紫杉醇诱导的周围神经病变 (PIPN)。本研究旨在探讨 PIPN 行为表现和潜在发病机制的性别差异，并寻找临床有效的干预措施。 将雄性和雌性 C57BL/6 小鼠（5-6 周和 12 个月，体重 18-30 g）腹腔注射（i.p.）。 )每隔一天以2mg/kg的剂量用盐水(NaCl 0.9%)稀释紫杉醇，总共注射4次。给药前后均进行Von Frey试验和热板试验，证实PIPN模型成功建立，并评价PIPN的疼痛情况和PD-L1的镇痛效果。 PTX 给药后第 14 天，通过鞘内 (i.t) 途径将 PD-L1 蛋白 (10ng/pc) 注射到 PIPN 中。为了敲低脊髓中的TRPV1，通过i.t缓慢注射腺相关病毒9（AAV9）-Trpv1-RNAi（5μL，1×1013 vg/mL）。路线。 AAV9 递送后 4 周，通过免疫荧光染色和蛋白质印迹验证了 TRPV1 表达的下调。通过Western blotting、RT-PCR和免疫荧光染色测定PD-L1、TRPV1和CGRP的水平。 RT-PCR检测TNF-α和IL-1β水平。对照雌性小鼠脊髓中TRPV1和CGRP蛋白和mRNA水平高于对照雄性小鼠脊髓。 TRPV1 和 CGRP 表达增加表明，雌性 PIPN 小鼠中 PTX 诱导的伤害行为大于雄性 PIPN 小鼠。 PD-L1 对机械痛觉过敏和热敏感性的镇痛作用在雌性小鼠中显着高于雄性小鼠，计算出的相对治疗水平分别增加了约 2.717 倍和 2.303 倍。 PD-L1 和 CGRP 与 TRPV1 部分共定位于小鼠脊髓背角。 PIPN 小鼠中 PD-L1 的镇痛作用是通过 AAV9 介导的脊髓特异性 TRPV1 表达下调后 TRPV1 和 CGRP 表达下调来介导的。PTX 诱导的 PIPN 小鼠伤害性行为和 PD-L1 的镇痛作用具有性别二态性，强调了将性别作为即将进行的 PIPN 机制研究中的关键生物学因素的重要性，并为潜在的性别特异性治疗方法提供了见解。© 2024 作者。中枢神经系统科学

Paclitaxel (PTX) is extensively utilized in the management of diverse solid tumors, frequently resulting in paclitaxel-induced peripheral neuropathy (PIPN). The present study aimed to investigate sex differences in the behavioral manifestations and underlying pathogenesis of PIPN and search for clinically efficacious interventions.Male and female C57BL/6 mice (5-6 weeks and 12 months, weighing 18-30 g) were intraperitoneally (i.p.) administered paclitaxel diluted in saline (NaCl 0.9%) at a dose of 2 mg/kg every other day for a total of 4 injections. Von Frey and hot plate tests were performed before and after administration to confirm the successful establishment of the PIPN model and also to evaluate the pain of PIPN and the analgesic effect of PD-L1. On day 14 after PTX administration, PD-L1 protein (10 ng/pc) was injected into the PIPN via the intrathecal (i.t.) route. To knock down TRPV1 in the spinal cord, adeno-associated virus 9 (AAV9)-Trpv1-RNAi (5 μL, 1 × 1013 vg/mL) was slowly injected via the i.t. route. Four weeks after AAV9 delivery, the downregulation of TRPV1 expression was verified by immunofluorescence staining and Western blotting. The levels of PD-L1, TRPV1 and CGRP were measured via Western blotting, RT-PCR, and immunofluorescence staining. The levels of TNF-α and IL-1β were measured via RT-PCR.TRPV1 and CGRP protein and mRNA levels were higher in the spinal cords of control female mice than in those of control male mice. PTX-induced nociceptive behaviors in female PIPN mice were greater than those in male PIPN mice, as indicated by increased expression of TRPV1 and CGRP. The analgesic effects of PD-L1 on mechanical hyperalgesia and thermal sensitivity were significantly greater in female mice than in male mice, with calculated relative therapeutic levels increasing by approximately 2.717-fold and 2.303-fold, respectively. PD-L1 and CGRP were partly co-localized with TRPV1 in the dorsal horn of the mouse spinal cord. The analgesic effect of PD-L1 in PIPN mice was observed to be mediated through the downregulation of TRPV1 and CGRP expression following AAV9-mediated spinal cord specific decreased TRPV1 expression.PTX-induced nociceptive behaviors and the analgesic effect of PD-L1 in PIPN mice were sexually dimorphic, highlighting the significance of incorporating sex as a crucial biological factor in forthcoming mechanistic studies of PIPN and providing insights for potential sex-specific therapeutic approaches.© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.