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Licensed Unlicensed Requires Authentication Published by De Gruyter February 15, 2019

Hyperpolarization-activated and cyclic nucleotide-gated channel proteins as emerging new targets in neuropathic pain

Jin-Ting He, Xiao-Yan Li, Xin Zhao and Xiaoliang Liu


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.

Funding source: Jilin Provincial Department of Finance Funds in China

Award Identifier / Grant number: Sczsy 201512

Funding source: Jilin Provincial Department of Health Funds

Award Identifier / Grant number: 20152085

Funding source: The National Natural Science Fund Projects

Award Identifier / Grant number: 81671159

Funding source: Jilin Province Department of International Cooperation Projects

Award Identifier / Grant number: 20170414014GH

Funding source: Jilin University Outstanding Young Teacher Training Program

Award Identifier / Grant number: 450060472325

Funding statement: This project was supported by the Jilin Provincial Department of Finance Funds in China (No. Sczsy 201512), the Jilin Provincial Department of Health Funds (No. 20152085), The National Natural Science Fund Projects (No. 81671159), the Jilin Province Department of International Cooperation Projects (No. 20170414014GH), and the Jilin University Outstanding Young Teacher Training Program (No. 450060472325).


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Received: 2018-09-12
Accepted: 2018-10-26
Published Online: 2019-02-15
Published in Print: 2019-07-26

©2019 Walter de Gruyter GmbH, Berlin/Boston

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