Donghoon Kima, Byunghyun Youa, Eun-Kyeong Job, Sang-Kyou Hanc, Melvin I. Simonc,1, and Sung Joong Leea,1
aProgram in Neuroscience, Dental Research Institute, and Brain Korea21, School of Dentistry, Seoul National University, Seoul, 110-749, Republic of Korea;
bDepartment of Microbiology and Infection Signaling Network Research Center, College of Medicine, Chungnam National University, Daejeon, 301-747,Republic of Korea; and
cDepartment of Pharmacology, University of California at San Diego, La Jolla, CA 92093
Contributed by Melvin I. Simon, July 8, 2010 (sent for review May 20, 2010)
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.
spinal nerve transection, sulforaphane
1To whom correspondence may be addressed.
Author contributions: D.K. and S.J.L. designed research; D.K. and B.Y. performed research; E.-K.J. contributed new reagents/analytic tools; S.-K.H., M.I.S., and S.J.L. analyzed data; and M.I.S. and S.J.L. wrote the paper.
The authors declare no conflict of interest.
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