Behavioral and immunohistological assessment of painful neuropathy induced by a single oxaliplatin injection in the rat
Behavioral and immunohistological assessment of painful neuropathy induced by a single oxaliplatin injection in the rat
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DOI：
10.1016/j.tox.2007.02.013
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发表时间：
2007-05-20
期刊：
影响因子：
4.5
通讯作者：
Authier, Nicolas
中科院分区：
文献类型：
--
作者：
Ling, Bing;Coudore-Civiale, Marie-Ange;Authier, Nicolas
在临床使用中，广泛用于治疗转移性结直肠癌的单次输注奥沙利铂会诱发因暴露于寒冷而引发或加剧的特定感觉神经毒性症状。为了研究这些症状的病理生理学，我们开发并表征了一种动物模型，该模型再现了单次腹腔内奥沙利铂给药（3、6和12 mg/kg）的效果。从 24 小时到第 5 天，迅速观察到对冷刺激的显着异常性疼痛和痛觉过敏，与对照相比，在 t+30 小时最大降低 76%。其他行为评估显示快速持续的机械异常性疼痛，但没有热痛觉过敏或热异常性疼痛，也没有对机械刺激的痛觉过敏。对脊髓背角浅层进行的免疫组织化学研究显示，与对照组相比，P 物质免疫反应性显着增加（12% 对 4%），而降钙素基因相关肽 (CGRP) 免疫反应性则没有变化。这种新的动物模型首次非常接近地模拟了单次奥沙铂输注后在人类中观察到的效果，特别是发作和高度强烈的感觉障碍、对寒冷的过敏并伴有异常性疼痛和痛觉过敏症状。该模型可能有助于阐明这种热超敏性的机制，特别是小直径 A 纤维可能参与冷异常性疼痛症状。这些选择性作用可能会揭示急性奥沙利铂神经病变的机制基础，从而更好地了解临床状况并优化其治疗。 (C) 2007 Elsevier Ireland Ltd. 保留所有权利。
In clinical use, a single infusion of oxaliplatin, widely used to treat metastatic colorectal cancer, induces specific sensory neurotoxicity signs triggered or aggravated by exposure to cold. To study the pathophysiology of these symptoms, we developed and characterized an animal model that reproduces the effects of a single intraperitoneal oxaliplatin administration (3, 6 and 12 mg/kg). Significant allodynia and hyperalgesia to cold stimuli were rapidly observed from 24 h to day 5 with a maximum lowering of 76% at t + 30 h versus control. Other behavioral assessments revealed rapid persistent mechanical allodynia, but no thermal hyperalgesia or allodynia to heat and no hyperalgesia to mechanical stimuli. An immunohistochernical study in the superficial layers of the spinal dorsal hom revealed a marked increase in substance P immunoreactivity versus controls (12% versus 4%), whereas calcitonin gene-related peptide (CGRP) immunoreactivity was unchanged. This new animal model for the first time closely mimics the effects observed in humans after a single oxatiplatin infusion, especially onset and highly intense sensory disturbances, hypersensitivity to cold with allodynia and hyperalgesia signs. This model may help to elucidate the mechanisms of this thermal hypersensitivity, especially the possible involvement of small-diameter A-fibers in cold allodynia symptoms. These selective effects may clue up the mechanistic basis for the acute oxaliplatin neuropathy leading to a better understanding of the clinical condition and to optimize its treatment. (C) 2007 Elsevier Ireland Ltd. All rights reserved.