Role of Drp1, a key mitochondrial fission protein, in neuropathic pain.
Role of Drp1, a key mitochondrial fission protein, in neuropathic pain.
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DOI：
10.1523/jneurosci.2223-11.2011
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发表时间：
2011-08-03
期刊：
影响因子：
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通讯作者：
Levine JD
中科院分区：
文献类型：
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作者：
Ferrari LF;Chum A;Bogen O;Reichling DB;Levine JD
虽然氧化应激与小纤维疼痛性周围神经病变有关，但抗氧化剂对治疗患者仅部分有效。我们已经测试了Drp 1（动力蛋白相关蛋白1）的假设，催化线粒体分裂的过程中，一种机制的作用和生产的活性氧（ROS）的核心GTdR，在这些神经性疼痛综合征中起着核心作用。鞘内注射反义Drp 1寡核苷酸可降低外周神经中Drp 1的表达，并显著减轻HIV/AIDS抗逆转录病毒（ddC）和抗癌（奥沙利铂）化疗引起的雄性Sprague道利大鼠神经病理性机械性痛觉过敏。为了证实Drp 1在这些神经性疼痛模型中的作用，以及证明其在感觉转导部位的贡献，我们在大鼠后爪背上的伤害性测试部位注射了高度选择性Drp 1抑制剂mdivi-1。Mdivi-1减弱了两种形式的神经性疼痛。为了评估Drp 1在ROS诱导的痛觉过敏中的作用，我们证明了皮内过氧化氢产生的剂量依赖性痛觉过敏可被mdivi-1抑制。最后，mdivi-1还抑制了由参与炎性和神经性疼痛的多种原伤害感受介质-肿瘤坏死因子α（TNFα）、胶质源性神经营养因子（GDNF）和一氧化氮（NO）诱导的机械性痛觉过敏。这些研究为线粒体分裂在炎症性和神经性疼痛的临床前模型中的重要作用提供了支持。
While oxidative stress has been implicated in small-fiber painful peripheral neuropathies, antioxidants are only partially effective to treat patients. We have tested the hypothesis that Drp1 (dynamin-related protein 1), a GTPase that catalyzes the process of mitochondrial fission, a mechanism central for the effect and production of reactive oxygen species (ROS), plays a central role in these neuropathic pain syndromes. Intrathecal administration of oligodeoxynucleotide antisense against Drp1 produced a decrease in its expression in peripheral nerve and markedly attenuated neuropathic mechanical hyperalgesia caused by HIV/AIDS anti-retroviral (ddC) and anti-cancer (oxaliplatin) chemotherapy in male Sprague Dawley rats. To confirm the role of Drp1 in these models of neuropathic pain, as well as to demonstrate its contribution at the site of sensory transduction, we injected a highly selective Drp1 inhibitor, mdivi-1, at the site of nociceptive testing on the dorsum of the rat’s hind paw. Mdivi-1 attenuated both forms of neuropathic pain. To evaluate the role of Drp1 in hyperalgesia induced by ROS, we demonstrated that intradermal hydrogen peroxide produced dose-dependent hyperalgesia that was inhibited by mdivi-1. Finally, mechanical hyperalgesia induced by diverse pronociceptive mediators involved in inflammatory and neuropathic pain – tumor necrosis factor alpha (TNFα), glial-derived neurotrophic factor (GDNF) and nitric oxide (NO) – was also inhibited by mdivi-1. These studies provide support for a substantial role of mitochondrial fission in preclinical models of inflammatory and neuropathic pain.