Suppression of HCN channels in the spinal dorsal horn restores KCC2 expression and attenuates diabetic neuropathic pain
Suppression of HCN channels in the spinal dorsal horn restores KCC2 expression and attenuates diabetic neuropathic pain
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DOI：
10.1016/j.neulet.2024.137626
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发表时间：
2024-01-12
影响因子：
2.5
通讯作者：
Liu，Xiaohong
中科院分区：
文献类型：
--
作者：
Ma，Yanqiao;Chen，Ji;Liu，Xiaohong
以往的研究表明，脊髓背角（SDH）超极化的环核苷酸门控（HCN）离子通道可能参与了糖尿病神经病理性疼痛（DNP）的发生。此外，其他研究表明，SDH中钾-氯协同转运蛋白2（KCC 2）表达的降低促进疼痛超敏反应。HCN通道和KCC 2在脊髓胶状质神经元中均呈高表达。然而，DNP中HCN通道激活所诱导的K+外流是否调节KCC 2的功能并随后影响神经元的γ-氨基丁酸（GABA）/GABA-A受体在SDH中的作用仍有待澄清。本工作的目的是研究KCC 2参与HCN通道促进DNP的潜在机制。在这里，我们发现HCN通道阻断剂ZD 7288的镇痛作用与KCC 2表达上调有关，并且可以被KCC 2阻断剂DIOA阻止。此外，DNP大鼠的GABA水平显著升高，ZD 72288可降低该水平。此外，DIOA预处理可部分阻断ZD 7288对DNP大鼠环磷酸腺苷-蛋白激酶A（cAMP-PKA）信号激活的抑制作用。最后，抑制cAMP-PKA信号传导减轻了DNP大鼠的异常性疼痛并提高了KCC 2的表达。总之，本研究揭示了cAMP PKA信号调节的HCN通道在DNP中的作用与脊髓中KCC 2表达的降低和GABA性质的改变有关。
Previous studies have shown that the hyperpolarized cyclic nucleotide gated (HCN) ion channels in the spinal dorsal horn (SDH) might be involved in the development of diabetic neuropathic pain (DNP). Additionally, other studies have shown that the decreased potassium-chloride cotransporter 2 (KCC2) expression in the SDH promotes pain hypersensitivity. Both HCN channels and KCC2 were highly expressed in spinal substantia gelatinosa neurons. However, whether the K+efflux induced by the activation of HCN channels in DNP modulate KCC2 function and subsequently affect the role of γ-aminobutyric acid (GABA)/GABA-A receptors of neurons in the SDH remains to be clarified. The purpose of this work was to investigate the underlying mechanisms of KCC2 participating in HCN channels to promote DNP. Here, we found that the analgesic role of HCN channels blocker ZD7288 was associated with the up-regulated KCC2 expression and could be prevented by DIOA, a KCC2 blocker. Furthermore, the level of GABA in DNP rats significantly increased, which was decreased by ZD72288. Moreover, DIOA pretreatment could partly block the inhibitory effect of ZD7288 on the cyclic adenosine monophosphate-protein kinase A (cAMP-PKA) signaling activation of DNP rats. Finally, inhibition of cAMP-PKA signaling alleviated allodynia and elevated KCC2 expression in DNP rats. Altogether, this study reveals that the role of cAMP-PKA signaling-regulated HCN channels in DNP associated with decreased KCC2 expression in the spinal cord and altered GABA nature.