# HCN2 channels: a potential therapeutic target for orofacial neuropathic pain after trigeminal nerve injury

## TL;DR

This study shows that HCN2 channels may be a new target for treating orofacial neuropathic pain after nerve injury.

## Contribution

The study identifies HCN2 channels as a novel therapeutic target for trigeminal neuropathic pain.

## Key findings

- CCI increased axonal HCN2 expression and reduced HWT in rats.
- Ivabradine improved pain by blocking HCN2 channels at the injury site.
- CCI altered cAMP-PKA-pCREB signaling, contributing to neuropathic pain.

## Abstract

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels have recently
emerged as promising targets for the treatment of neuropathic pain. This study
investigated the potential involvement of HCN2 channels in the development of
trigeminal neuropathic pain following peripheral nerve injury. Infraorbital nerve
chronic constriction injury (ION-CCI) model was adopted to rats, and head
withdrawal thresholds (HWT) to mechanical stimulation were assessed pre- and
postoperatively, as well as after pharmacological intervention. In the trigeminal
ganglion (TG), intracellular cyclic adenosine monophosphate (cAMP) and
cytoplasmic protein kinase A (PKA) levels were quantified by Enzyme-Linked
Immunosorbent Assay (ELISA), while Hcn2 mRNA expression was evaluated by
quantitative Polymerase Chain Reaction (qPCR). Immunohistochemical analysis was
performed to assess phosphorylated cAMP response element-binding protein (pCREB)
expression in the TG and HCN2 expression in infraorbital nerve (ION) axons. In
the TG, cAMP and pCREB levels were elevated, whereas cytoplasmic PKA and Hcn2
mRNA levels were reduced. Axonal HCN2 expression was increased in CCI rats. On
day 14, HWT was significantly reduced following CCI but was ameliorated by local
administration of the HCN channel blocker ivabradine at the site of axonal
injury. Collectively, these findings suggest that CCI-induced alterations in
cAMP-PKA-pCREB signaling promote HCN2 accumulation in injured axons, thereby
contributing to the development of orofacial neuropathic pain following
peripheral nerve injury.