Pharmazentrum Frankfurt/ZAFES, Institut für Klinische Pharmakologie, Klinikum der Johann Wolfgang Goethe-Universität, 60590 Frankfurt am Main, Germany.
J Neurosci. 2012 Jul 25;32(30):10136-45. doi: 10.1523/JNEUROSCI.6227-11.2012.
Reactive oxygen species (ROS) contribute to sensitization of pain pathways during neuropathic pain, but little is known about the primary sources of ROS production and how ROS mediate pain sensitization. Here, we show that the NADPH oxidase isoform Nox4, a major ROS source in somatic cells, is expressed in a subset of nonpeptidergic nociceptors and myelinated dorsal root ganglia neurons. Mice lacking Nox4 demonstrated a substantially reduced late-phase neuropathic pain behavior after peripheral nerve injury. The loss of Nox4 markedly attenuated injury-induced ROS production and dysmyelination processes of peripheral nerves. Moreover, persisting neuropathic pain behavior was inhibited after tamoxifen-induced deletion of Nox4 in adult transgenic mice. Our results suggest that Nox4 essentially contributes to nociceptive processing in neuropathic pain states. Accordingly, inhibition of Nox4 may provide a novel therapeutic modality for the treatment of neuropathic pain.
活性氧 (ROS) 在神经病理性疼痛期间有助于痛觉通路的敏化，但对于 ROS 产生的主要来源以及 ROS 如何介导痛觉敏化知之甚少。在这里，我们表明 NADPH 氧化酶同工型 Nox4 是体细胞中主要的 ROS 来源，它在非肽能伤害感受器和有髓背根神经节神经元的亚群中表达。缺乏 Nox4 的小鼠在周围神经损伤后表现出明显减轻的晚期神经病理性疼痛行为。Nox4 的缺失显著减弱了损伤诱导的外周神经 ROS 产生和脱髓鞘过程。此外，在成年转基因小鼠中用他莫昔芬诱导 Nox4 缺失后，持续的神经病理性疼痛行为受到抑制。我们的研究结果表明，Nox4 对于神经病理性疼痛状态下的伤害性处理至关重要。因此，抑制 Nox4 可能为治疗神经病理性疼痛提供一种新的治疗模式。
