# Sodium Channel Nav1.6 in Chemotherapy-Induced Pain

> **NIH VA I01** · VA CONNECTICUT HEALTHCARE SYSTEM · 2023 · —

## Abstract

Over the past decade, our multi-disciplinary studies combining molecular genetics, cell biology, ion channel
biophysics, sensory neuron physiology, and behavioral analysis have pinpointed the role of sodium channel
NaV1.6 in pain. Our goal now is to investigate the contribution of NaV1.6 to chemotherapy-induced pain and
peripheral neuropathy (CIPPN), and to determine whether genetic variants of Nav1.6 can influence
susceptibility to pain mediated by chemotherapeutic drugs. These studies will inform treatment options for pain
and personalized, pharmacogenomics-based strategies in prescribing chemotherapy to cancer patients.
Chemotherapy is frequently associated with sodium channelopathy and the development of neuropathy.
Furthermore, studies implicating NaV1.6 in CIPPN show enhanced persistent and resurgent currents in DRG
neurons following treatment with the chemotherapeutic agent oxaliplatin. Recent work from our lab has
suggested involvement of Nav1.6 in pain induced by vincristine, another chemotherapeutic agent. However,
the pathophysiology and pharmacology of vincristine-induced pain (VIP) including underlying genetic risk
factors remain unclear. Our goal in this proposal is to investigate Nav1.6—an essential channel for action
potential propagation in myelinated fibers—in CIPPN to: a) Establish the role of Nav1.6 in VIP; b) Inform
pharmacogenomics-based chemotherapy to avert development of CIPPN; and c) Develop a novel non-opioid
based treatment strategy that targets Nav1.6
We will apply the following research design and methods to achieve our goal.
Specific Aim 1: Assess the contribution of Nav1.6 to VIP in vivo. Our preliminary data from embryonic
knockout studies of Nav1.6 suggests a contribution by this channel to VIP. However, it is possible that
compensatory mechanisms may confound observed outcomes. Here, we will knockout Nav1.6 in adult mice to
assess the following metrics that can better inform future translational studies in adult subjects.
Specific Aim 2: Assess genetic variations in Nav1.6 as a risk factor for VIP. Not all patients who undergo
chemotherapy develop CIPPN, which suggests that genetic variations may underlie exaggerated response to
chemotherapy. Our laboratory was the first to show that gain-of-function (GOF) variants of Nav1.6 can cause
epilepsy, a disorder similar to neuropathic pain that reflects underlying neuronal hyperexcitability. We have
also recently identified a GOF variant in NaV1.6 (Met136Val) in a patient with painful trigeminal neuralgia,
which suggests that this variant may predispose the carrier to the development of disease. NaV1.6-M136V
channels increase amplitude of transient and resurgent currents and increase neuronal firing. In this specific
aim we will examine whether NaV1.6-M136V exacerbates VIP in a mouse model.
Specific Aim 3: Assess the use of cannabinoids to ameliorate VIP. Cannabidiol (CBD) is FDA-approved
for treatment of some forms of epilepsy and has been shown to block resurgent NaV...

## Key facts

- **NIH application ID:** 10700086
- **Project number:** 5I01RX003621-03
- **Recipient organization:** VA CONNECTICUT HEALTHCARE SYSTEM
- **Principal Investigator:** Sulayman D Dib-Hajj
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2023
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2021-11-01 → 2025-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10700086

## Citation

> US National Institutes of Health, RePORTER application 10700086, Sodium Channel Nav1.6 in Chemotherapy-Induced Pain (5I01RX003621-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10700086. Licensed CC0.

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