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

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 produc...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2010-08, Vol.107 (33), p.14851-14856
Main Authors: Kim, Donghoon, You, Byunghyun, Jo, Eun-Kyeong, Han, Sang-Kyou, Simon, Melvin I., Lee, Sung Joong
Format: Article
Language:English
Subjects:
Animals
Biological Sciences
Blotting, Western
Cells, Cultured
CYBB protein
Cytokines
Dorsal horn
Gene Expression
Hyperalgesia
Hyperalgesia - physiopathology
Hyperalgesia - prevention & control
Hypersensitivity
Immunohistochemistry
Inflammation
Injections, Spinal
Interleukin-1beta - genetics
Interleukin-1beta - metabolism
Isothiocyanates
Male
Membrane Glycoproteins - genetics
Membrane Glycoproteins - metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Microglia
Microglia - cytology
Microglia - metabolism
NAD(P)H oxidase
NADPH Oxidase 2
NADPH Oxidases - genetics
NADPH Oxidases - metabolism
Neuralgia - etiology
Neuralgia - physiopathology
Neuralgia - prevention & control
Neurons
Neuropathy
Oxygen
Pain
Pain Measurement - methods
Pain perception
Peripheral Nerve Injuries
Peripheral nerves
Peripheral nervous system diseases
Posterior horn
Rats
Rats, Sprague-Dawley
Reactive oxygen species
Reactive Oxygen Species - metabolism
Reverse Transcriptase Polymerase Chain Reaction
Rodents
Spinal cord
Spinal Cord - metabolism
Spinal cord injuries
Spinal cord injury
Spinal nerves
Sulforafan
Thiocyanates - administration & dosage
Thiocyanates - pharmacology
Tumor Necrosis Factor-alpha - genetics
Tumor Necrosis Factor-alpha - metabolism
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1009926107