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A3063
October 13, 2014
1:00 PM - 2:30 PM
Room Room 244
An IL-1 Receptor Antagonist Improves Anxiety-Like Behavior Induced by Chronic Neuropathic Pain Via the Blockade of Phosphorylationof NMDA receptors on Neurons in the Amygdala
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

Chronic neuropathic pain causes emotional abnormalities such as anxiety and depression. Recently, expression of inflammatory cytokines in the brain has been reported to be the possible mechanism of the development of anxiety. At the American Society of Anesthesiologists 2013 annual meeting, we gave a presentation showing that neuropathic pain induced anxiety-like behavior in partial sciatic nerve ligation (PSNL)-treated mice at day 28 after surgery and, at the same time, bone marrow-derived microglia (BMDM) that expressed high levels of interleukin (IL)-1β infiltrated in the central nucleus of the amygdala (CeA). We investigated the effects of intracerebroventricular injection (ICV) and microinjection into the CeA of an IL-1 receptor (IL-1R) antagonist on anxiety-like behavior and hypersensitivity induced by 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. To confirm BMDM-neuron interaction within the CeA via IL-1β/IL-1R, immunohistochemical overlap staining was performed at day 28 after surgery. ICV injection of a low dose (0.9 μg) and a high dose (1.8 μg) of an IL-1R antagonist was performed in PSNL-treated mice at days 27 and 28. We investigated the effects of ICV injection of the IL-1R antagonist on anxiety-like behavior and hypersensitivity induced by neuropathic pain at day 28 after surgery. We also evaluated the effect of ICV injection of the IL-1R antagonist on phosphorylation of NMDA receptors on neurons in the CeA and spinal cord by immunohistochemistry. Microinjection into the CeA of the IL-1R antagonist (9 ng) was performed in PSNL-treated mice at day 28. We investigated the effects of microinjection into the CeA of the IL-1R antagonist on anxiety-like behavior and hypersensitivity induced by neuropathic pain at day 28. 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

BMDM expressed IL-1β and neurons expressed IL-1R in the CeA of PSNL-treated mice at day 28 after surgery. ICV injection of both low and high doses of the IL-1R antagonist reversed anxiety-like behavior induced by neuropathic pain to normal levels. ICV injection of a low dose of the IL-1R antagonist did not reverse hypersensitivity, whereas ICV injection of a high dose of the IL-1R antagonist partially reversed hypersensitivity induced by neuropathic pain. Although neurons in the CeA and spinal cord expressed phosphorylated NMDA receptors (pNMDARs) in PSNL-treated mice, neurons in the CeA did not express pNMDARs in PSNL-treated mice with ICV injection of a low dose of the the IL-1R antagonist. Furthermore, neurons in the CeA and spinal cord did not express pNMDARs in PSNL-treated mice with ICV injection of a high dose of the IL-1R antagonist. Microinjection into the CeA of the IL-1R antagonist reversed anxiety-like behavior to normal levels but did not reverse hypersensitivity induced by neuropathic pain.

Conclusion

It has been reported that IL-1β enhances excitatory postsynaptic currents through the phosphorylation of NMDA receptors via IL-1R. ICV injection and microinjection into the CeA of an IL-1R antagonist reversed anxiety-like behavior via the blockade of phosphorylation of NMDA receptors on neurons in the CeA. As shown in the present study, blockade of IL-1R in the CeA successfully reversed the anxiety-like behavior in PSNL-treated mice, suggesting that neuron-microglia interactions between IL-1β and pNMDARs in the CeA might be important in neuropathic pain-induced anxiety.

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