Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, MO 63104, USA.
Neurosci Lett. 2010 Oct 11;483(2):85-9. doi: 10.1016/j.neulet.2010.07.013. Epub 2010 Jul 14.
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.
超氧化物及其活性副产物过氧亚硝酸盐作为伤害性信号转导的介质的作用正在显现。我们最近报告称，脊髓线粒体超氧化物歧化酶（MnSOD）的硝化和失活为与吗啡诱导的痛觉过敏和抗伤害性耐受发展相关的中枢敏化期间这些活性氧和氮物种的一个关键来源。在这项研究中，我们证明了脊髓 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性耐受的发展与 NADPH 氧化酶的激活和超氧化物的释放增加有关。吗啡与两种结构上无关的 NADPH 氧化酶抑制剂即 apocynin 或二苯基碘（DPI）的全身给药共同给药，阻断了 NADPH 氧化酶的激活以及痛觉过敏和抗伤害性耐受的发展，而这些剂量没有行为副作用。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抗伤害性耐受的发展。通过显示鞘内给予 apocynin 阻断了这些事件，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的酶源，从而作为吗啡诱导的痛觉过敏和抗伤害性耐受相关的中枢敏化的过氧亚硝酸盐的贡献。这些结果继续支持这些活性氧和氮物种在疼痛中的关键作用，同时推进了我们对其生物分子来源的认识。
