Rattus norvegicus strain:Wistar | cultivar:HAN Transcriptome or Gene expression

Chemotherapy-induced neuropathic pain (CINP) is a common adverse health related comorbidity that manifests later in life in paediatric cancer patients. Current analgesia is ineffective, aligning closely with our lack of understanding of CINP. The aim of this study was to investigate how cisplatin induces nerve growth factor mediated neuroinflammation and nociceptor sensitisation. In a rodent model of cisplatin induced survivorship pain, cisplatin induced a neuroinflammatory environment in the dorsal root ganglia (DRG) demonstrated by nerve growth factor (NGF) positive macrophages infiltrating into the DRG. Cisplatin treated CD11b/F480 positive macrophages expressed more NGF compared to vehicle treated. Primary DRG sensory neuronal cultures demonstrated enhanced NGF-dependent TRPV1 mediated nociceptor activity after cisplatin treatment. Increased nociceptor activity was also observed when cultured DRG neurons were treated with conditioned media from cisplatin activated macrophages. Elevated nociceptor activity was dose-dependently inhibited by a neutralising NGF antibody. Intraperitoneal administration of a NGF neutralising antibody reduced cisplatin-induced mechanical hypersensitivity and aberrant nociceptor intraepidermal nerve fibre density. These findings identify that a monocyte/macrophage driven NGF/TrkA pathway is a novel analgesic target for adult survivors of childhood cancer.

化疗诱导神经性疼痛（Chemotherapy-induced neuropathic pain, CINP）是儿科癌症患者晚年常见的健康相关不良共病症。当前镇痛治疗效果欠佳，这与我们对CINP的认知不足密切相关。本研究旨在探究顺铂如何诱导神经生长因子（nerve growth factor, NGF）介导的神经炎症与痛觉感受器致敏。在顺铂诱导存活期疼痛的啮齿动物模型中，顺铂可在背根神经节（dorsal root ganglia, DRG）内诱导形成神经炎症环境，该现象可通过浸润至DRG的NGF阳性巨噬细胞得以证实。与溶媒处理组相比，经顺铂处理的CD11b/F480阳性巨噬细胞可表达更多的NGF。原代背根神经节感觉神经元培养实验显示，顺铂处理后，依赖NGF的瞬时受体电位香草酸亚型1（Transient receptor potential vanilloid 1, TRPV1）介导的痛觉感受器活性显著升高。当使用顺铂激活的巨噬细胞的条件培养基处理培养的DRG神经元时，同样可观察到痛觉感受器活性升高。中和性NGF抗体可剂量依赖性地抑制升高的痛觉感受器活性。腹腔注射中和性NGF抗体可减轻顺铂诱导的机械痛敏以及异常的痛觉感受器表皮内神经纤维密度。本研究结果证实，单核细胞/巨噬细胞驱动的NGF/酪氨酸激酶受体A（Tyrosine kinase receptor A, TrkA）通路可作为儿童癌症成年存活患者的新型镇痛靶点。