Early life cisplatin exposure induces nerve growth factor mediated neuroinflammation and chemotherapy induced neuropathic pain.

IF 4 3区 医学 Q2 CELL BIOLOGY
Marlene Da Vitoria Lobo, Lydia Hardowar, Tameille Valentine, Lucy Tomblin, Charlotte Guest, Dhyana Sharma, Benjamin Dickins, Mark Paul-Clark, Richard Philip Hulse
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Abstract

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.

早年接触顺铂会诱发神经生长因子介导的神经炎症和化疗引起的神经病理性疼痛。
化疗引起的神经病理性疼痛(CINP)是一种常见的与健康相关的不良并发症,在儿童癌症患者中表现为晚期疼痛。目前的镇痛效果不佳,这与我们对 CINP 缺乏了解密切相关。本研究旨在探讨顺铂如何诱导神经生长因子介导的神经炎症和痛觉感受器敏感化。在顺铂诱导存活痛的啮齿动物模型中,顺铂诱导背根神经节(DRG)的神经炎症环境,表现为神经生长因子(NGF)阳性巨噬细胞渗入DRG。经顺铂处理的 CD11b/F480 阳性巨噬细胞比经药物处理的巨噬细胞表达更多的 NGF。经顺铂处理后,DRG 原始感觉神经元培养物显示出 NGF 依赖性 TRPV1 介导的痛觉感受器活性增强。用顺铂活化巨噬细胞的条件培养基处理 DRG 神经元培养物时,也观察到痛觉感受器活性增强。中和 NGF 抗体对痛觉感受器活性的升高有剂量依赖性抑制作用。腹腔注射 NGF 中和抗体可降低顺铂诱导的机械过敏性和表皮内神经纤维密度异常。这些研究结果表明,单核细胞/巨噬细胞驱动的NGF/TrkA通路是儿童癌症成年幸存者的新型镇痛靶点。
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来源期刊
Disease Models & Mechanisms
Disease Models & Mechanisms 医学-病理学
CiteScore
6.60
自引率
7.00%
发文量
203
审稿时长
6-12 weeks
期刊介绍: Disease Models & Mechanisms (DMM) is an online Open Access journal focusing on the use of model systems to better understand, diagnose and treat human disease.
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