• Masaaki Kobayashi, Hiroyuki Konishi, Akira Sayo, Toshiyuki Takai, and Hiroshi Kiyama.
• Department of Functional Anatomy and Neuroscience, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
• J. Neurosci. 2016 Oct 26; 36 (43): 11138-11150.

AbstractNeuropathic pain afflicts millions of people, and the development of an effective treatment for this intractable pain is an urgent issue. Recent evidence has implicated microglia in neuropathic pain. The present study showed that the DNAX-activating protein of 12 kDa (DAP12) and its associated "triggering receptor expressed on myeloid cells 2" (TREM2) were predominantly expressed by microglia in the dorsal horn after spinal nerve injury, revealing a role for TREM2/DAP12 signaling in neuropathic pain. Nerve injury-induced proinflammatory cytokine expression in microglia and pain behaviors were significantly suppressed in Dap12-deficient mice. Furthermore, intrathecal administration of TREM2 agonistic antibody induced proinflammatory cytokine expression, as well as neuropathic pain, in mice without nerve injury. The agonistic antibody induced proinflammatory responses and neuropathic pain was not observed in Dap12-deficient mice. Together, these results suggest that TREM2/DAP12-mediated signals in microglia exacerbate nerve injury-induced neuropathic pain by inducing proinflammatory cytokine secretion from microglia. Suppression of DAP12-mediated signals could be a therapeutic target for neuropathic pain.Copyright © 2016 the authors 0270-6474/16/3611138-13$15.00/0.

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