Effects of mitochondrial poisons on the neuropathic pain produced by the chemotherapeutic agents, paclitaxel and oxaliplatin.
Effects of mitochondrial poisons on the neuropathic pain produced by the chemotherapeutic agents, paclitaxel and oxaliplatin.
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DOI：
10.1016/j.pain.2011.12.011
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发表时间：
2012-03
期刊：
影响因子：
7.4
通讯作者：
Bennett GJ
中科院分区：
文献类型：
--
作者：
Xiao WH;Bennett GJ
紫杉烷、铂络合物和其他种类的抗癌药物的剂量限制性副作用是慢性、远端、双侧对称的感觉性周围神经病变，其通常伴有神经性疼痛。这些条件的动物模型的工作表明，神经病变是对初级传入感觉神经元中的线粒体的毒性作用的结果。如果这是真的，那么额外的线粒体损伤应该会使神经性疼痛恶化。这一预测在因紫杉烷类药物紫杉醇和铂复合物药物奥沙利铂而患有疼痛性周围神经病变的大鼠中进行了测试。患有神经病变的大鼠被给予三种线粒体毒物之一：鱼藤酮（呼吸复合物I的抑制剂），寡霉素（ATP合成酶的抑制剂）和金诺芬（硫氧还蛋白-硫氧还蛋白还原酶线粒体抗氧化防御系统的抑制剂）。所有这三种毒素都显著增加了紫杉醇诱发和奥沙利铂诱发的机械异常性疼痛和机械痛觉过敏的严重程度，而对化疗初治大鼠的机械敏感性没有影响。化疗诱发的疼痛性周围神经病变与初级传入A纤维和C纤维的异常自发放电有关。寡霉素，在相同的剂量，加剧异常性疼痛和痛觉过敏，显着增加了自发放电的A-纤维和C-纤维的放电频率在紫杉醇治疗和奥沙利铂治疗的大鼠，但没有引起任何放电在幼稚对照大鼠。这些结果表明，线粒体功能障碍在化疗引起的神经性疼痛的生产，并表明，药物，对线粒体功能有积极的影响，可能是在其治疗和预防使用。
The dose-limiting side-effect of taxane, platinum-complex, and other kinds of anti-cancer drugs is a chronic, distal, bilaterally symmetrical, sensory peripheral neuropathy that is often accompanied by neuropathic pain. Work with animal models of these conditions suggests that the neuropathy is a consequence of toxic effects on mitochondria in primary afferent sensory neurons. If this is true, then additional mitochondrial insult ought to make the neuropathic pain worse. This prediction was tested in rats with painful peripheral neuropathy due to the taxane agent, paclitaxel, and the platinum-complex agent, oxaliplatin. Rats with established neuropathy were given one of three mitochondrial poisons: rotenone (an inhibitor of respiratory Complex I), oligomycin (an inhibitor of ATP synthase), and auranofin (an inhibitor of the thioredoxin-thioredoxin reductase mitochondrial anti-oxidant defense system). All three toxins significantly increased the severity of paclitaxel-evoked and oxaliplatin-evoked mechano-allodynia and mechano-hyperalgesia while having no effect on the mechano-sensitivity of chemotherapy naïve rats. Chemotherapy-evoked painful peripheral neuropathy is associated with an abnormal spontaneous discharge in primary afferent A-fibers and C-fibers. Oligomycin, at the same dose that exacerbated allodynia and hyperalgesia, significantly increased the discharge frequency of spontaneously discharging A-fibers and C-fibers in both paclitaxel-treated and oxaliplatin-treated rats, but did not evoke any discharge in naïve control rats. These results implicate mitochondrial dysfunction in the production of chemotherapy-evoked neuropathic pain and suggest that drugs that have positive effects on mitochondrial function may be of use in its treatment and prevention.
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