Antioxidant activity of sestrin 2 controls neuropathic pain after peripheral nerve injury

Antioxid Redox Signal. 2013 Dec 10;19(17):2013-23. doi: 10.1089/ars.2012.4958. Epub 2013 Apr 19.


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 well-characterized model of neuropathic pain. Sesn2 knockout (Sesn2(-/-)) mice exhibited considerably increased late-phase 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-α-phenylnitrone. In contrast, administration of the ROS donor tert-butyl 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 ROS-dependent neuropathic pain signaling after peripheral nerve injury and may, thus, provide a potential new target for the clinical management of chronic neuropathic pain conditions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 3 / metabolism
  • Animals
  • Antioxidants / physiology
  • Female
  • Ganglia, Spinal / metabolism
  • Hyperalgesia / chemically induced
  • Hyperalgesia / metabolism
  • Hyperalgesia / pathology
  • Inflammation / chemically induced
  • Inflammation / metabolism
  • Inflammation / pathology
  • Male
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neuralgia / metabolism*
  • Nociception
  • Nuclear Proteins / physiology*
  • Peripheral Nerve Injuries / metabolism*
  • Peripheral Nerve Injuries / pathology
  • Peroxidases
  • Reactive Oxygen Species / metabolism
  • Sensory Receptor Cells / metabolism
  • Up-Regulation
  • Zymosan


  • Activating Transcription Factor 3
  • Antioxidants
  • Atf3 protein, mouse
  • Nuclear Proteins
  • Reactive Oxygen Species
  • Zymosan
  • Peroxidases
  • Sesn2 protein, mouse