HC-030031 allodynia chemotherapy melanoma nociception paclitaxel
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摘要

Antineoplastic therapy has been associated with pain syndrome development characterized by acute and chronic pain. The chemotherapeutic agent dacarbazine, used mainly to treat metastatic melanoma, is reported to cause painful symptoms, compromising patient quality of life. Evidence has proposed that transient receptor potential ankyrin 1 (TRPA1) plays a critical role in chemotherapy-induced pain syndrome. Here, we investigated whether dacarbazine causes painful hypersensitivity in naive or melanoma-bearing mice and the involvement of TRPA1 in these models. Mouse dorsal root ganglion (DRG) neurons and human TRPA1-transfected HEK293 (hTRPA1-HEK293) cells were used to evaluate the TRPA1-mediated calcium response evoked by dacarbazine. Mechanical and cold allodynia were evaluated after acute or repeated dacarbazine administration in naive mice or after inoculation of B16-F10 melanoma cells in C57BL/6 mice. TRPA1 involvement was investigated by using pharmacological and genetic tools (selective antagonist or antisense oligonucleotide treatment and Trpa1 knockout mice). Dacarbazine directly activated TRPA1 in hTRPA1-HEK293 cells and mouse DRG neurons and appears to sensitize TRPA1 indirectly by generating oxidative stress products. Moreover, dacarbazine caused mechanical and cold allodynia in naive but not Trpa1 knockout mice. Also, dacarbazine-induced nociception was reduced by the pharmacological TRPA1 blockade (antagonism), antioxidants, and by ablation of TRPA1 expression. TRPA1 pharmacological blockade also reduced dacarbazine-induced nociception in a tumor-associated pain model. Thus, dacarbazine causes nociception by TRPA1 activation, indicating that this receptor may represent a pharmacological target for treating chemotherapy-induced pain syndrome in cancer patients submitted to antineoplastic treatment with dacarbazine.

译文

抗肿瘤治疗与以急性和慢性疼痛为特征的疼痛综合征的发展有关。据报道,主要用于治疗转移性黑色素瘤的化疗药物达卡巴嗪会引起疼痛症状,损害患者的生活质量。有证据表明,瞬时受体电位锚蛋白 1 (TRPA1) 在化疗引起的疼痛综合征中起着关键作用。在这里,我们研究了达卡巴嗪是否在初治或荷黑素瘤小鼠中引起疼痛超敏反应,以及 TRPA1 在这些模型中的参与。用小鼠背根神经节 (DRG) 神经元和人 TRPA1-transfected HEK293 (hTRPA1-HEK293) 细胞评价达卡巴嗪诱发的 TRPA1-mediated 钙反应。在初代小鼠中急性或反复给予达卡巴嗪或在 C57BL/6 小鼠中接种 B16-F10 黑素瘤细胞后,评估机械和冷性变态反应。通过药理学和遗传学工具 (选择性拮抗剂或反义寡核苷酸治疗和 TRPA1 基因敲除小鼠) 研究 Trpa1 的参与。达卡巴嗪直接激活 hTRPA1-HEK293 细胞和小鼠 DRG 神经元中的 TRPA1,并通过产生氧化应激产物间接敏感 TRPA1。此外,达卡巴嗪引起了幼稚而非 Trpa1 基因敲除小鼠的机械性变态反应和冷性变态反应。同样,达卡巴嗪诱导的伤害感受被药理学上的 TRPA1 阻断 (拮抗作用) 、抗氧化剂和 TRPA1 表达的消融所减少。TRPA1 药物阻断还降低了肿瘤相关疼痛模型中达卡巴嗪诱导的伤害感受。因此,达卡巴嗪通过 TRPA1 激活引起伤害感受,表明该受体可能代表治疗癌症患者提交达卡巴嗪抗肿瘤治疗的化疗引起的疼痛综合征的药理目标。

Hypersensitivity

免疫 超敏反应 疾病
概述  :  

超敏反应,又称为变态反应,是自身免疫系统敏感性过高出现的一系列反应,是指机体受到某些抗原刺激时出现生理功能紊乱或组织细胞损伤的异常适应性免疫应答。免疫系统针对抗原如食物、药物、花粉、尘螨、动物毛发等过于敏感而发生的免疫应答,并对自身造成损伤。 分类 根据超敏反应发生机制和临床特点,将其分为Ⅰ、Ⅱ、Ⅲ、Ⅳ四型。四型超敏反应其效应T细胞、抗原、效应机制及临床常见疾病存在明显差异。 1.Ⅰ型超敏反应主要由IgE抗体介导,无补体参

hypersensitivity   英 /ˌhaɪpəˌsensəˈtɪvəti/ 美 /ˌhaɪpərˌsensəˈtɪvəti/

释义    n. 过敏症;超敏反应,过度敏感

短语    Hypersensitivity reaction 超敏反应;过敏反应;超敏反映

例句    Hypersensitivity pneumonitis is related to inhaled antigens.过敏性肺炎与吸入抗原物质有关。

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