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BOS11
October 13, 2014
8:00 AM - 10:00 AM
Room Room 265-268
A CCR2 Antagonist Suppresses Infiltration of Bone Marrow-Derived Microglia Into the Central Nervous System and Reverses Anxiety-Like Behavior As Well As Hypersensitivity Induced by Chronic Neuropathic Pain
Atsushi Sawada, M.D., Ph.D., Yukitoshi Niiyama, M.D., Ph.D., Michiaki Yamakage, M.D., Ph.D.
Sapporo Medical University School of Medicine, Sapporo, Japan
Background

Anxiety disorder is a common complication of neuropathic pain. Microglia are classified into two subtypes: resident microglia, which are innate immune-related glial cells of the central nervous system (CNS), and bone marrow-derived microglia (BMDM), which infiltrate into the CNS from the blood in various clinical situations. Psychological stress has been reported to promote infiltration of BMDM into the brain and induce anxiety-like behavior. In addition, several studies have shown that monocyte chemotactic protein-1 (MCP-1) and its receptor, C-C chemokine receptor type 2 (CCR2), participate in infiltration of BMDM into the CNS. We investigated the effects of a CCR2 antagonist on infiltration of BMDM into the CNS, anxiety-like behavior, and hypersensitivity induced by chronic neuropathic pain.

Materials and Methods

The Animal Care and Use Committee of our university approved the protocol. Adult male C57BL/6 mice received bone marrow transplantation from green fluorescent protein C57BL/6 transgenic mice. At day 28 after bone marrow transplantation, model mice were subjected to partial sciatic nerve ligation (PSNL) to induce neuropathic pain. In sham mice, the sciatic nerve was exposed without ligation. We quantified the expression of BMDM in the brain by immunohistochemistry at days 7, 14, 21, and 28 after surgery. Total RNA was extracted from sorted microglia or isolated amygdala tissue at day 28 after surgery. Quantitative RT-PCR for the expression of CCR2 and CXC chemokine receptor 4 (CXCR4) in isolated microglia and for the expression of MCP-1 and stromal cell-derived factor 1 (SDF-1) in amygdala tissue was performed. To confirm the expression of MCP-1 in amygdala tissue by immunohistochemistry, we counted the number of MCP-1+/Neuronal Nuclei (NeuN)+ cells in the central nucleus of the amygdala (CeA) at days 7, 21, and 28 after surgery. A CCR2 antagonist, RS102895, was administered orally with gavage twice a day from days 21 to 28. We investigated the effects of RS102895 on infiltration of BMDM into the CNS, anxiety-like behavior, and hypersensitivity induced by chronic neuropathic pain in PSNL-treated mice at day 28 after surgery. Data were analyzed using two-tailed Student’s t-test or repeated measures ANOVA followed by Tukey’s Multiple Comparison Test. Differences were considered significant at P < 0.05.

Results

Neuropathic pain induced hypersensitivity from days 1 to 28 and anxiety-like behavior in PSNL-treated mice at day 28 after surgery. At day 28, BMDM infiltrated into the CeA but were scarcely distributed in other areas of the brain in PSNL-treated mice. BMDM were not detected in any areas of the brain in sham-treated mice. For chemokine receptors, mRNA expressions for CCR2 and CXCR4 were significantly increased in BMDM. Although the expression of SDF-1 in amygdala tissue was unchanged, the mRNA expression of MCP-1 in amygdala tissue of PSNL-treated mice was significantly increased. The number of MCP-1+/NeuN+ cells in the CeA was increased in PSNL-treated mice at day 28 after surgery. RS102895 suppressed the infiltration of BMDM into the CNS and reversed anxiety-like behavior as well as hypersensitivity induced by chronic neuropathic pain.

Conclusion

Neuropathic pain induced anxiety-like behavior and promoted infiltration of BMDM in the CeA via the MCP-1/CCR2 axis in PSNL-treated mice at day 28 after surgery. A CCR2 antagonist suppressed the infiltration of BMDM into the CNS and reversed anxiety-like behavior as well as hypersensitivity induced by chronic neuropathic pain. These findings indicate that a CCR2 antagonist is a new possibility for the treatment of anxiety-like behavior and hypersensitivity induced by chronic neuropathic pain.

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