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Nav1.8: Intrinsic limits on the functional effect of abrogation in DRG neurons
Dmytro V Vasylyev1,2, Peng Zhao1,2, Betsy R Schulman1,2
1Department of Neurology and Center for Neuroscience and Regeneration Research, Yale School of Medicine, New Haven, CT 06510.
Summary
Voltage-gated sodium channel Nav1.8 influences neuron excitability and pain. Inhibiting Nav1.8 can reduce neuropathic pain, but targeting other channels may be needed for complete relief due to varying neuron responses.
Area of Science:
- Neuroscience
- Pharmacology
- Ion Channel Physiology
Background:
- Voltage-gated sodium channel Nav1.8 is vital for small dorsal root ganglion (DRG) neuron excitability.
- Nav1.8 is a promising therapeutic target for managing pain.
- Gain-of-function Nav1.7 mutations cause inherited erythromelalgia, a human pain disorder.
Purpose of the Study:
- To investigate the role of Nav1.8 conductance in action potential (AP) generation and firing properties.
- To assess the impact of manipulating Nav1.8 on native DRG neurons and those with a gain-of-function Nav1.7 mutation.
- To evaluate Nav1.8 as a therapeutic target for neuropathic pain.
Main Methods:
- Utilized dynamic clamp to systematically alter Nav1.8 conductance in rat DRG neurons.
- Examined effects on AP electrogenesis, rheobase, and repetitive firing.
- Studied neurons expressing wild-type Nav1.8 and the Nav1.7L858H mutation.
Main Results:
- Nav1.8 conductance strongly correlated with AP voltage threshold and regulated AP overshoot.
- Two distinct populations of DRG neurons were identified: strong responders (50%) and weak responders (50%) to Nav1.8 modulation.
- In hyperexcitable neurons, partial Nav1.8 inhibition normalized rheobase in 63% of cells, but 37% remained hyperexcitable.
Conclusions:
- Nav1.8 inhibition effectively reduces neuropathic pain in responsive DRG neurons.
- The existence of weakly responsive DRG neurons suggests that co-targeting other ion channels may be necessary for comprehensive pain relief.
- Findings highlight the complexity of targeting Nav1.8 for pain therapeutics.
