Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, 1402 South Grand Boulevard, St. Louis, MO 63104, USA.
Neuroscience. 2013 Jun 25;241:1-9. doi: 10.1016/j.neuroscience.2013.02.042. Epub 2013 Feb 27.
The analgesic effectiveness of long-term opioid therapies is compromised by the development of antinociceptive tolerance linked to the overt production of peroxynitrite (ONOO(-), PN), the product of the interaction between superoxide (O2(-), SO) and nitric oxide (NO), and to neuroinflammatory processes. We have recently reported that in addition to post-translational nitration and inactivation of mitochondrial manganese superoxide dismutase (MnSOD), activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase holoenzyme (NOX) in the spinal cord is a major source for the overt production of superoxide-derived PN during the development of morphine-induced antinociceptive tolerance. However, the NOX complex involved in these processes is not known. The objective of these studies is to identify a potential role for the NOX2 complex, an enzyme involved in inflammation. Mice lacking the catalytic subunit of NOX2 (Nox2(-/-)) or its regulatory subunit, p47(phox) (p47(phox)(-/-)), developed antinociceptive tolerance similar to wildtype (wt) mice after 3 days of continuous morphine. However, while wt mice continue to develop tolerance by day six, morphine analgesia was restored in both Nox2(-/-) and p47(phox)(-/-) mice. Moreover, the loss of Nox2 or p47 did not affect acute morphine analgesia in naïve mice. In wt mice, antinociceptive tolerance was associated with increased activation of NOX, nitration of MnSOD, and proinflammatory cytokines production in the spinal cord. These events were markedly attenuated in Nox2(-/-) and p47(phox)(-/-) mice and instead, there was enhanced formation of antiinflammatory cytokine (IL4 and IL10) production. These results suggest that NOX2 activity provides a significant source of superoxide-derived PN to undertake post-translational modifications of mitochondrial MnSOD and to engage neuroinflammatory signaling in the spinal cord associated with opioid-induced antinociceptive tolerance. Thus, NOX2 may provide a potential target for adjuvant therapy to protect opioid analgesia.
长期阿片类药物治疗的镇痛效果受到抗伤害性耐受的影响，这种耐受与过氧化物亚硝酸盐（ONOO(-)，PN）的产生有关，而 PN 是超氧化物（O2(-)，SO）和一氧化氮（NO）相互作用的产物，也与神经炎症过程有关。我们最近报道，除了线粒体锰超氧化物歧化酶（MnSOD）的翻译后硝化和失活外，脊髓中烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶全酶（NOX）的激活也是吗啡诱导的抗伤害性耐受发展过程中超氧化物衍生 PN 产生的主要来源。然而，目前尚不清楚这些过程中涉及的 NOX 复合物。本研究旨在确定参与炎症的 NOX2 复合物在这些过程中的潜在作用。缺乏 NOX2 催化亚基（Nox2(-/-)）或其调节亚基 p47(phox)（p47(phox)(-/-)）的小鼠在连续给予吗啡 3 天后，与野生型（wt）小鼠一样发展出抗伤害性耐受。然而，尽管 wt 小鼠在第 6 天继续发展耐受，但吗啡镇痛作用在 Nox2(-/-)和 p47(phox)(-/-)小鼠中均得到恢复。此外，Nox2 或 p47 的缺失并不影响新生小鼠的急性吗啡镇痛作用。在 wt 小鼠中，抗伤害性耐受与脊髓中 NOX 的激活、MnSOD 的硝化和促炎细胞因子的产生增加有关。这些事件在 Nox2(-/-)和 p47(phox)(-/-)小鼠中明显减弱，而抗炎细胞因子（IL4 和 IL10）的产生增加。这些结果表明，NOX2 活性为超氧化物衍生 PN 提供了一个重要来源，用于进行线粒体 MnSOD 的翻译后修饰，并参与与阿片类药物诱导的抗伤害性耐受相关的脊髓神经炎症信号。因此，NOX2 可能为保护阿片类药物镇痛的辅助治疗提供一个潜在的靶点。
