# Structural basis of venom peptides that inhibit a Na+ channel regulator of pain

> **NIH NIH P20** · UNIVERSITY OF OKLAHOMA · 2021 · $151,287

## Abstract

Chronic pain and opioid abuse cause human suffering and impose a burden on public health systems. A 
better understanding of the mechanisms that block transmission of pain signals would advance efforts to 
develop non-addictive pain drugs. Pain-pathway neurons transmit signals to the brain via action potentials. 
The voltage-gated sodium channel (VGSC) Nav1.8 is a protein pore that regulates the flux of Na+ across 
the membranes of nociceptive neurons, producing the action potentials that carry pain signals to the brain. 
Injury, aging and disease cause biochemical changes in neurons that activate Nav1.8 to initiate action 
potentials. Inactivation of Nav1.8 halts the transmission of pain signals. The mechanisms that govern 
inactivation provide a strategy for developing non-addictive pain drugs. Venom peptides from scorpions 
provide a toolkit for investigating inactivation mechanisms. For example, cryo-electron microscopy studies 
using scorpion peptides bound to Nav1.7, a channel responsible for spontaneous pain disorders, revealed 
the structural basis of fast inactivation. However, studying Nav1.8 inactivation mechanisms has proved 
challenging. While Nav1.8 has been linked to neuropathic and inflammatory pain, highlighting the potential 
for Nav1.8 to serve as an alternative drug target to Nav1.7, the mechanisms that regulate inactivation are 
not completely understood. Progress has been hindered by a lack of venom peptides that modify Nav1.8 
gating. Arizona bark scorpion venom inhibits Nav1.8 and blocks pain in species of predatory mice. This 
study will use computational modeling to predict docking trajectories between inhibitory peptides and 
Nav1.8. The structural basis for peptide inhibition of Nav1.8 will be characterized by 1) mapping binding 
sites between peptides and the channel, and 2) building computational models of the peptide-Nav1.8 
complex. Computational models of peptide-bound channels will reveal the structural basis for Nav1.8 
gating. These goals are significant because inactivation is critical for regulating Nav1.8 activity and pain 
signal transmission. Knowledge of the biophysical and molecular bases for peptide-mediated inhibition of 
Nav1.8 would provide structural guides for engineering non-addictive pain drugs.

## Key facts

- **NIH application ID:** 10415506
- **Project number:** 5P20GM103640-10
- **Recipient organization:** UNIVERSITY OF OKLAHOMA
- **Principal Investigator:** ASHLEE Hedgecock ROWE
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $151,287
- **Award type:** 5
- **Project period:** 2021-06-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10415506

## Citation

> US National Institutes of Health, RePORTER application 10415506, Structural basis of venom peptides that inhibit a Na+ channel regulator of pain (5P20GM103640-10). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10415506. Licensed CC0.

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