TrpA1 activation in peripheral sensory neurons underlies the ionic basis of pain hypersensitivity in response to vinca alkaloids.
TrpA1 activation in peripheral sensory neurons underlies the ionic basis of pain hypersensitivity in response to vinca alkaloids.
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DOI：
10.1371/journal.pone.0186888
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Eaton BA
中科院分区：
文献类型：
--
作者：
Boiko N;Medrano G;Montano E;Jiang N;Williams CR;Madungwe NB;Bopassa JC;Kim CC;Parrish JZ;Hargreaves KM;Stockand JD;Eaton BA
化疗引起的周围神经病变 (CIPN) 是包括长春花生物碱在内的许多抗癌药物的副作用，其特点是严重疼痛综合征，影响了许多患者的治疗。目前除了减少抗癌药物剂量外，还没有针对这种疼痛综合征的有效治疗方法。现有数据支持这样的模型：与 CIPN 相关的疼痛是抗癌药物增强外周感觉伤害感受器功能的结果，但抗癌药物对感觉神经元功能影响的细胞机制尚未得到很好的描述。动物模型研究表明了许多疾病病因，包括线粒体毒性、轴突变性、免疫信号传导和感觉神经支配减少，但这些结果是长期治疗模式的结果，并不一定代表与 CIPN 相关的早期形成事件。在这里，我们发现，急性接触长春花生物碱会导致果蝇和小鼠立即出现疼痛综合征。此外，我们证明，将分离的感觉神经元暴露于长春花生物碱会导致产生内向钠电流，能够使这些神经元去极化至阈值，从而导致神经元放电。长春花生物碱的这些神经元作用需要瞬时受体电位锚蛋白-1 (TrpA1) 通道，并且在 TrpA1 突变果蝇和小鼠中，急性暴露于长春花生物碱时对疼痛刺激的超敏反应会减少。这些发现证明了引起 CIPN 的化疗药物对感觉神经元的直接兴奋，并将 TrpA1 确定为 CIPN 发病机制中的重要靶点。
Chemotherapy induced peripheral neuropathy (CIPN), a side effect of many anti-cancer drugs including the vinca alkaloids, is characterized by a severe pain syndrome that compromises treatment in many patients. Currently there are no effective treatments for this pain syndrome except for the reduction of anti-cancer drug dose. Existing data supports the model that the pain associated with CIPN is the result of anti-cancer drugs augmenting the function of the peripheral sensory nociceptors but the cellular mechanisms underlying the effects of anti-cancer drugs on sensory neuron function are not well described. Studies from animal models have suggested a number of disease etiologies including mitotoxicity, axonal degeneration, immune signaling, and reduced sensory innervations but these outcomes are the result of prolonged treatment paradigms and do not necessarily represent the early formative events associated with CIPN. Here we show that acute exposure to vinca alkaloids results in an immediate pain syndrome in both flies and mice. Furthermore, we demonstrate that exposure of isolated sensory neurons to vinca alkaloids results in the generation of an inward sodium current capable of depolarizing these neurons to threshold resulting in neuronal firing. These neuronal effects of vinca alkaloids require the transient receptor potential ankyrin-1 (TrpA1) channel, and the hypersensitization to painful stimuli in response to the acute exposure to vinca alkaloids is reduced in TrpA1 mutant flies and mice. These findings demonstrate the direct excitation of sensory neurons by CIPN-causing chemotherapy drugs, and identify TrpA1 as an important target during the pathogenesis of CIPN.
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