Spinal NADPH oxidase is a source of superoxide in the development of morphine-induced hyperalgesia and antinociceptive tolerance.
Spinal NADPH oxidase is a source of superoxide in the development of morphine-induced hyperalgesia and antinociceptive tolerance.
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脊髓 NADPH 氧化酶是吗啡引起的痛觉过敏和镇痛耐受中超氧化物的来源。
DOI：
10.1016/j.neulet.2010.07.013
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发表时间：
2010-10-11
影响因子：
2.5
通讯作者：
Salvemini, Daniela
中科院分区：
文献类型：
--
作者：
Doyle, Tim;Bryant, Leesa;Muscoli, Carolina;Cuzzocrea, Salvatore;Esposito, Emanuela;Chen, Zhoumou;Salvemini, Daniela
超氧化物及其活性副产物过氧亚硝酸盐作为伤害性信号传导介质的作用正在显现。我们最近报道，脊髓线粒体超氧化物歧化酶（MnSOD）的硝化和失活在与吗啡诱导的痛觉过敏和镇痛耐受的发展相关的中枢敏化过程中提供了这些活性氧和氮物种的关键来源。在这项研究中，我们证明脊髓 NADPH 氧化酶的激活是超氧化物产生的另一个关键来源。事实上，吗啡诱导的痛觉过敏和抗伤害耐受的发生与 NADPH 氧化酶的激活和超氧化物释放的增加有关。吗啡与两种结构不相关的 NADPH 氧化酶抑制剂（即罗布麻宁或二亚苯基碘鎓 (DPI)）的全身给药联合给药，在没有行为副作用的剂量下阻断了 NADPH 氧化酶的激活以及痛觉过敏和镇痛耐受的发展。这些结果表明脊髓 NADPH 氧化酶的激活有助于吗啡诱导的痛觉过敏和镇痛耐受的发展。通过鞘内递送罗布麻素可阻断这些事件，证实了脊髓 NADPH 氧化酶的作用。我们的结果首次表明 NADPH 氧化酶作为超氧化物和过氧亚硝酸盐的酶源在与吗啡诱导的痛觉过敏和镇痛耐受相关的中枢敏化发展中的贡献。这些结果继续支持这些活性氧和氮在疼痛中的关键作用，同时增进了我们对其生物分子来源的了解。
The role of superoxide and its active byproduct peroxynitrite as mediators of nociceptive signaling is emerging. We have recently reported that nitration and inactivation of spinal mitochondrial superoxide dismutase (MnSOD) provides a critical source of these reactive oxygen and nitrogen species during central sensitization associated with the development of morphine-induced hyperalgesia and antinociceptive tolerance. In this study, we demonstrate that activation of spinal NADPH oxidase is another critical source for superoxide generation. Indeed, the development of morphine-induced hyperalgesia and antinociceptive tolerance was associated with increased activation of NADPH oxidase and superoxide release. Co-administration of morphine with systemic delivery of two structurally unrelated NADPH oxidase inhibitors namely apocynin or diphenyleneiodonium (DPI), blocked NADPH oxidase activation and the development of hyperalgesia and antinociceptive tolerance at doses devoid of behavioral side effects. These results suggest that activation of spinal NADPH oxidase contributes to the development of morphine-induced hyperalgesia and antinociceptive tolerance. The role of spinal NADPH oxidase was confirmed by showing that intrathecal delivery of apocynin blocked these events. Our results are the first to implicate the contribution of NADPH oxidase as an enzymatic source of superoxide and thus peroxynitrite in the development of central sensitization associated with morphine-induced hyperalgesia and antinociceptive tolerance. These results continue to support the critical role of these reactive oxygen and nitrogen species in pain while advancing our knowledge of their biomolecular sources.
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