Department of Oral and Maxillofacial Surgery, Graduate School of Dentistry, Faculty of Dental Science, Kyushu University, Fukuoka 812‑8582, Japan.
Department of Aging Science and Pharmacology, Faculty of Dental Science, Kyushu University, Fukuoka 812‑8582, Japan.
Int J Mol Med. 2019 Oct;44(4):1585-1593. doi: 10.3892/ijmm.2019.4279. Epub 2019 Jul 19.
Neuropathic pain is one of most intense types of chronic pain. Numerous studies investigating neuropathic pain have described the critical involvement of microglia in the spinal cord. Previous studies have indicated that activation of large conductance Ca2+‑activated K+ (BK) channels contributes to microglial activation in the spinal dorsal horn (SDH) and the generation of neuropathic pain. However, the specific role of BK channels in spinal microglia in neuropathic pain has not been fully addressed in previous studies, as BK channel inhibitors were used to inhibit microglial BK channel based on their inhibitory kinetics. We previously identified that Ca2+‑activated K+ channel β3 auxiliary subunit (KCNMB3), which is an auxiliary subunit of BK channels and regulates gating properties of the channel, is exclusively expressed in microglia in the spinal cord. The present study analyzed the role of BK channels in spinal microglia in neuropathic pain using a spinal microglia‑specific BK channel knockdown method, with intrathecal injection of KCNMB3 small interfering RNA. Neuropathic pain was significantly attenuated in KCNMB3 knockdown mice. Increases in the number of microglia in the SDH following nerve injury were attenuated by KCNMB3 knockdown. Furthermore, increased levels of pain‑associated molecules in the SDH were attenuated in KCNMB3 knockdown mice. Attempts were also made to analyze the effects of KCNMB3 knockdown on chronic pain. KCNMB3 knockdown ameliorated chronic pain and inhibited the expression levels of pain‑associated molecules in the SDH. The results from the present study suggested that BK channels modulated the activation state of spinal microglia, and that KCNMB3 is a potential therapeutic target for neuropathic pain.
神经病理性疼痛是最剧烈的慢性疼痛类型之一。许多研究神经病理性疼痛的研究描述了小胶质细胞在脊髓中的关键作用。先前的研究表明，大电导钙激活钾（BK）通道的激活有助于脊髓背角（SDH）中小胶质细胞的激活和神经病理性疼痛的产生。然而，BK 通道在神经病理性疼痛中的脊髓小胶质细胞中的具体作用在以前的研究中尚未得到充分解决，因为 BK 通道抑制剂是基于其抑制动力学来抑制小胶质细胞 BK 通道的。我们之前发现，Ca2+激活的钾通道β3 辅助亚基（KCNMB3）是 BK 通道的辅助亚基，调节通道的门控特性，仅在脊髓中的小胶质细胞中表达。本研究使用鞘内注射 KCNMB3 小干扰 RNA 的方法，分析了 BK 通道在神经病理性疼痛中脊髓小胶质细胞中的作用。在 KCNMB3 敲低小鼠中，神经病理性疼痛明显减轻。神经损伤后 SDH 中小胶质细胞数量的增加被 KCNMB3 敲低所减弱。此外，KCNMB3 敲低小鼠 SDH 中疼痛相关分子的水平升高也被减弱。本研究还试图分析 KCNMB3 敲低对慢性疼痛的影响。KCNMB3 敲低减轻了慢性疼痛，并抑制了 SDH 中疼痛相关分子的表达水平。本研究结果表明，BK 通道调节脊髓小胶质细胞的激活状态，KCNMB3 是治疗神经病理性疼痛的潜在靶点。
