Emerging lines of evidence indicate that production of reactive oxygen species (ROS) at distinct sites of the nociceptive system contributes to the processing of neuropathic pain. However, the mechanisms underlying ROS production during neuropathic pain processing are not fully understood. We here detected the ROS-generating nicotinamide adenine dinucleotide phosphate oxidase isoform Nox2 in macrophages of dorsal root ganglia (DRG) in mice. In response to peripheral nerve injury, Nox2-positive macrophages were recruited to DRG, and ROS production was increased in a Nox2-dependent manner. Nox2-deficient mice displayed reduced neuropathic pain behavior after peripheral nerve injury, whereas their immediate responses to noxious stimuli were normal. Moreover, injury-induced upregulation of tumor necrosis factor α was absent, and activating transcription factor 3 induction was reduced in DRG of Nox2-deficient mice, suggesting an attenuated macrophage-neuron signaling. These data suggest that Nox2-dependent ROS production in macrophages recruited to DRG contributes to neuropathic pain hypersensitivity, underlining the observation that Nox-derived ROS exert specific functions during the processing of pain.
Aims: Neuropathic pain is a chronic debilitating disease that is often unresponsive to currently available treatments. Emerging lines of evidence indicate that reactive oxygen species (ROS) are required for the development and maintenance of neuropathic pain. However, little is known about endogenous mechanisms that neutralize the pain-relevant effects of ROS. In the present study, we tested whether the stress-responsive antioxidant protein Sestrin 2 (Sesn2) blocks the ROS-induced neuropathic pain processing in vivo. Results: We observed that Sesn2 mRNA and protein expression was up-regulated in peripheral nerves after spared nerve injury, a wellcharacterized model of neuropathic pain. Sesn2 knockout (Sesn2 -/ -) mice exhibited considerably increased latephase neuropathic pain behavior, while their behavior in acute nociceptive and in inflammatory pain models remained unaffected. The exacerbated neuropathic pain behavior of Sesn2 -/ -mice was associated with elevated ROS levels and an enhanced activating transcription factor 3 up-regulation in sensory neurons, and it was reversed by the ROS scavenger N-tert-Butyl-a-phenylnitrone. In contrast, administration of the ROS donor tertbutyl hydroperoxide induced a prolonged pain behavior in naive Sesn2-/ -mice. Innovation: We show that the antioxidant function of Sesn2 limits neuropathic pain processing in vivo. Conclusion: Sesn2 controls ROSdependent neuropathic pain signaling after peripheral nerve injury and may, thus, provide a potential new target for the clinical management of chronic neuropathic pain conditions.
Our results suggest that oxidant-induced activation of cGKIα specifically contributes to neuropathic pain processing, and that prevention of cGKIα redox activation could be a potential novel strategy to manage neuropathic pain.
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