Astrocyte activation in the spinal dorsal horn may play an important role in the development of chronic neuropathic pain, but the mechanisms involved in astrocyte activation and their modulatory effects remain unknown. The inward rectifying potassium channel protein 4.1 (Kir4.1) is the most important background K⁺ channel in astrocytes. However, how Kir4.1 is regulated and contributes to behavioral hyperalgesia in chronic pain is unknown. In this study, single-cell RNA sequencing analysis indicated that the expression levels of both Kir4.1 and Methyl-CpG-binding protein 2 (MeCP2) were decreased in spinal astrocytes after chronic constriction injury (CCI) in a mouse model. Conditional knockout of the Kir4.1 channel in spinal astrocytes led to hyperalgesia, and overexpression of the Kir4.1 channel in spinal cord relieved CCI-induced hyperalgesia. Expression of spinal Kir4.1 after CCI was regulated by MeCP2. Electrophysiological recording in spinal slices showed that knockdown of Kir4.1 significantly up-regulated the excitability of astrocytes and then functionally changed the firing patterns of neurons in dorsal spinal cord. Therefore, targeting spinal Kir4.1 may be a therapeutic approach for hyperalgesia in chronic neuropathic pain.

脊髓背角星形胶质细胞的激活可能在慢性神经性疼痛的发展中发挥重要作用，但星形胶质细胞激活的机制及其调节作用仍不清楚。内向整流钾通道蛋白4.1 (Kir4.1) 是星形胶质细胞中最重要的背景K ⁺通道。然而，Kir4.1 如何受到调节并导致慢性疼痛中的行为痛觉过敏尚不清楚。在这项研究中，单细胞 RNA 测序分析表明，在小鼠模型中慢性压迫性损伤 (CCI) 后，脊髓星形胶质细胞中 Kir4.1 和甲基 CpG 结合蛋白 2 (MeCP2) 的表达水平均下降。脊髓星形胶质细胞中 Kir4.1 通道的条件性敲除会导致痛觉过敏，脊髓中 Kir4.1 通道的过度表达可缓解 CCI 诱导的痛觉过敏。CCI后脊髓Kir4.1的表达受MeCP2调节。脊髓切片的电生理记录表明，Kir4.1 的敲低显着上调了星形胶质细胞的兴奋性，然后功能性地改变了背侧脊髓神经元的放电模式。因此，靶向脊髓 Kir4.1 可能是慢性神经性疼痛痛觉过敏的一种治疗方法。