Hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels are activated during hyperpolarization, and there is an inward flow of current, which is termed as hyperpolarization-activated current, Ih. Initially, these channels were identified on the pacemaker cells of the heart. Nowadays, these are identified on different regions of the nervous system, including peripheral nerves, dorsal root ganglia, dorsal horns, and different parts of the brain. There are four different types of HCN channels (HCN1–HCN4); however, HCN1 and HCN2 are more prominent. A large number of studies have shown that peripheral nerve injury increases the amplitude of Ih current in the neurons of the spinal cord and the brain. Moreover, there is an increase in the expression of HCN1 and HCN2 protein channels in peripheral axons and the spinal cord and brain regions in experimental models of nerve injury. Studies have also documented the pain-attenuating actions of selective HCN inhibitors, such as ivabradine and ZD7288. Moreover, certain drugs with additional HCN-blocking activities have also shown pain-attenuating actions in different pain models. There have been few studies documenting the relationship of HCN channels with other mediators of pain. Nevertheless, it may be proposed that the HCN channel activity is modulated by endogenous opioids and cyclo-oxygenase-2, whereas the activation of these channels may modulate the actions of substance P and the expression of spinal N-methyl-D-aspartate receptor subunit 2B to modulate pain. The present review describes the role and mechanisms of HCN ion channels in the development of neuropathic pain.

中文翻译：

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超极化激活和环核苷酸门控通道蛋白作为神经性疼痛的新靶点

超极化激活和环核苷酸门控（HCN）通道在超极化过程中被激活，并且存在向内流动的电流，称为超极化激活电流，IH. 最初，这些通道是在心脏的起搏器细胞上识别出来的。如今，这些被识别在神经系统的不同区域，包括周围神经、背根神经节、背角和大脑的不同部位。有四种不同类型的 HCN 通道（HCN1-HCN4）；然而，HCN1 和 HCN2 更为突出。大量研究表明，周围神经损伤会增加 IH脊髓和大脑神经元中的电流。此外，在神经损伤实验模型中，外周轴突和脊髓和大脑区域中 HCN1 和 HCN2 蛋白通道的表达增加。研究还记录了选择性 HCN 抑制剂（如伊伐布雷定和 ZD7288）的镇痛作用。此外，某些具有额外 HCN 阻断活性的药物在不同的疼痛模型中也显示出减轻疼痛的作用。很少有研究记录 HCN 通道与其他疼痛介质的关系。然而，可以提出 HCN 通道活性受内源性阿片类药物和 cyclo-oxygenase-2 的调节，而这些通道的激活可能会调节 P 物质的作用和脊髓 N-甲基-D-天冬氨酸受体亚基 2B 的表达以调节疼痛。本综述描述了 HCN 离子通道在神经性疼痛发展中的作用和机制。