# Using FHF2 to Adjust the Gain on Pain

> **NIH VA IK1** · VA CONNECTICUT HEALTHCARE SYSTEM · 2021 · —

## Abstract

The prevalence of chronic pain is higher in Veterans compared to the civilian population. Current treatments
rely heavily on the use of opioids. The lack of adequate alternative treatments has led to overuse of opioids in
the management of pain. These facts highlight the urgent need for alternative pain treatment options.
The work outlined in this proposal will focus on voltage-gated sodium channel Nav1.7, an important component
in human pain signaling. Single amino acid mutations in Nav1.7 cause at least two known diseases in humans
related to pain. Mutations that lead to an increase in activity in the channel cause inherited erythromelalgia
(IEM) a chronic pain syndrome that manifests as heat-induced burning pain in the distal extremities. Other
mutations in the same channel that lead to decreased activity in Nav1.7 cause congenital insensitivity to pain
(CIP) in which patients do not feel pain, i.e., they suffer from painless bone fractures, burns and childbirth.
Because of this validation in human cases, Nav 1.7 has emerged as an attractive target in the treatment of
chronic pain.
The proposed research will build upon recently published work, which demonstrated that FGF homologous
factor 2 (FHF2) interacts with Nav1.7, and that knockdown of FHF2 in native dorsal root ganglion (DRG)
neurons results in increased Nav1.7 activity. This work will utilize a gene therapy approach to determine
whether overexpression of FHF2 can confer loss-of-function attributes to Nav1.7 activity and thereby attenuate
nociceptor excitability (a proxy for pain) after nerve injury.
This proposal aims to further elucidate the mechanisms linking nerve damage to neuronal hyperexcitability. It
has been shown that FHF2 is downregulated after nerve axotomy. Knockdown of FHF2 leads to gain-of-
function changes in Nav1.7 activity, and Nav1.7 has been linked to neuronal hyperexcitability. We will utilize
an RNA interference approach to knockdown FHF2 levels in an isoform dependent manner and measure the
effects on neuronal excitability using multielectrode array analysis, in order to determine that FHF2 is an
important factor in a mechanism that links nerve damage to hyperexcitability and pain. We will further
investigate the mechanism underlying observed changes in excitability using current clamp electrophysiology.
A deeper understanding of this mechanism might reveal additional opportunities to target the mechanism of
FHF2 induced Nav1.7 modulation as a way of attenuating neuropathic pain after nerve injury.
The ultimate goal of this research program is to discover an alternative way to treat chronic pain of neuropathic
origin. This work will have applications for treating both trauma and burn related neuropathic pain, and if
successful, will have an important impact on improving the quality of life of Veterans afflicted with pain.

## Key facts

- **NIH application ID:** 10237203
- **Project number:** 5IK1RX003374-02
- **Recipient organization:** VA CONNECTICUT HEALTHCARE SYSTEM
- **Principal Investigator:** Philip Effraim
- **Activity code:** IK1 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2020-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10237203

## Citation

> US National Institutes of Health, RePORTER application 10237203, Using FHF2 to Adjust the Gain on Pain (5IK1RX003374-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10237203. Licensed CC0.

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