Pacemaking Activity in the Peripheral Nervous System: Physiology and Roles of Hyperpolarization Activated and Cyclic Nucleotide-Gated Channels in Neuropathic Pain.

Fan Liu,Ronak Bahuva,Boula S Gattas,Eugeniu Stratulat,Muhammad Ahsan Shafiq,George Y Wuni,Domonick K Gordon,Crystal N Ibetoh

doi:10.7759/cureus.11111

Abstract

The most famous pacemaking activity found in the human body is in the cardiac system. However, pacemaking is also widely present in the nervous system. The ion channels responsible for the pacemaking activity are called hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels. HCN channels are activated during hyperpolarization and create an inward current named Ih containing mixed sodium and potassium ions. The molecular mechanism of these unique features remains mysterious. In the peripheral nervous system (PNS), pacemaking is unique because it is only present in pathologic states when nerve damage occurs and leads to neuropathic pain. For this reason, pacemaking in neuropathic pain is also known as ectopic discharge. In our literature review, the HCN channel physiology is one of the research interests. We will present studies exploring the molecular mechanisms involved in HCN gating and ion permeability. The second research question is, what makes the pacemaking activity unique in the PNS? Thus, our paper will include studies that discuss the role of HCN channels in neuropathic pain. Given the fundamental role of HCN channels in regulating neuronal cells' discharge activity, the modulation of their function for therapeutic purposes could be useful in various pathological conditions. Here we review the present knowledge of the efficacy of HCN blocker treating neuropathic pain in humans.

Highlights

BackgroundAs a fundamental physiological process, pacemaking is one of the most attractive topics for investigators
These findings demonstrate that hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels play an essential role in spontaneous neuronal discharge originating in the damaged large-sized neuron of dorsal root ganglion (DRG) [35]
The non-traumatic model demonstrates that HCN2 has an essential role in both inflammatory and neuropathic pain because the elevated cyclic adenosine monophosphate (cAMP) produced by the COX/prostaglandin E2 (PGE2) pathway is the crucial mediator for HCN2 activation

Summary

Introduction

As a fundamental physiological process, pacemaking is one of the most attractive topics for investigators. Thanks to the development of electrophysiological techniques in the late 19th to early 20th century, Noma and Irisawa were the first research group that discovered a unique current [2] This current was quite "funny" or "queer" because it was an inward current, and the activation occurred during hyperpolarization [3]. In the late 20th century, different research groups collectively discovered the ion channels responsible for this "funny" current. In their molecular studies, the ion channel was a cyclic nucleotide-gated channel with proved to have pacemaking characteristics. How to cite this article Liu F, Wuni G Y, Bahuva R, et al (October 23, 2020) Pacemaking Activity in the Peripheral Nervous System: Physiology and Roles of Hyperpolarization Activated and Cyclic Nucleotide-Gated Channels in Neuropathic Pain. We will review the clinical trial that tests the efficacy of ivabradine as an analgesic drug

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Siegel RE