NADPH oxidase 2-derived reactive oxygen species in spinal cord microglia contribute to peripheral nerve injury-induced neuropathic pain

Proc Natl Acad Sci U S A. 2010 Aug 17;107(33):14851-6. doi: 10.1073/pnas.1009926107. Epub 2010 Aug 2.

Abstract

Increasing evidence supports the notion that spinal cord microglia activation plays a causal role in the development of neuropathic pain after peripheral nerve injury; yet the mechanisms for microglia activation remain elusive. Here, we provide evidence that NADPH oxidase 2 (Nox2)-derived ROS production plays a critical role in nerve injury-induced spinal cord microglia activation and subsequent pain hypersensitivity. Nox2 expression was induced in dorsal horn microglia immediately after L5 spinal nerve transection (SNT). Studies using Nox2-deficient mice show that Nox2 is required for SNT-induced ROS generation, microglia activation, and proinflammatory cytokine expression in the spinal cord. SNT-induced mechanical allodynia and thermal hyperalgesia were similarly attenuated in Nox2-deficient mice. In addition, reducing microglial ROS level via intrathecal sulforaphane administration attenuated mechanical allodynia and thermal hyperalgesia in SNT-injured mice. Sulforaphane also inhibited SNT-induced proinflammatory gene expression in microglia, and studies using primary microglia indicate that ROS generation is required for proinflammatory gene expression in microglia. These studies delineate a pathway involving nerve damage leading to microglial Nox2-generated ROS, resulting in the expression of proinflammatory cytokines that are involved in the initiation of neuropathic pain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Cells, Cultured
  • Gene Expression
  • Hyperalgesia / physiopathology
  • Hyperalgesia / prevention & control
  • Immunohistochemistry
  • Injections, Spinal
  • Interleukin-1beta / genetics
  • Interleukin-1beta / metabolism
  • Isothiocyanates
  • Male
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microglia / cytology
  • Microglia / metabolism*
  • NADPH Oxidase 2
  • NADPH Oxidases / genetics
  • NADPH Oxidases / metabolism*
  • Neuralgia / etiology
  • Neuralgia / physiopathology*
  • Neuralgia / prevention & control
  • Pain Measurement / methods
  • Peripheral Nerve Injuries
  • Rats
  • Rats, Sprague-Dawley
  • Reactive Oxygen Species / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Spinal Cord / metabolism
  • Thiocyanates / administration & dosage
  • Thiocyanates / pharmacology
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Interleukin-1beta
  • Isothiocyanates
  • Membrane Glycoproteins
  • Reactive Oxygen Species
  • Thiocyanates
  • Tumor Necrosis Factor-alpha
  • Cybb protein, mouse
  • NADPH Oxidase 2
  • NADPH Oxidases
  • sulforafan