Contusive spinal cord injury causes Nav1.8 dysfunction to upregulate small sensory neuron excitability.

Area of Science:

• Neuroscience
• Pain Research
• Molecular Biology

Background:

• Chronic neuropathic pain following spinal cord injury (SCI) is a significant unmet medical need.
• Peripheral neuron hyperexcitability, particularly in dorsal root ganglion (DRG) neurons, is implicated in SCI-associated pain.
• The precise molecular mechanisms driving these peripheral changes after SCI remain largely unknown.

Purpose of the Study:

• To investigate the role of sodium channel dysfunction in DRG neurons following SCI.
• To identify molecular targets and potential therapeutic interventions for SCI-induced neuropathic pain.

Main Methods:

• Electrophysiological recordings were performed on small diameter rat DRG neurons following contusive SCI.
• Analysis focused on transient and resurgent sodium currents, specifically involving Nav1.8 and Nav1.9 channels.
• The effects of ZL0177, a fibroblast growth factor homologous factor 4 (FHF4) peptidomimetic, were assessed on sodium currents and neuronal excitability.

Main Results:

• Contusive SCI significantly increased transient and resurgent sodium currents, primarily mediated by Nav1.8, in small DRG neurons.
• SCI elevated the proportion of DRG neurons exhibiting tetrodotoxin-resistant resurgent currents.
• ZL0177 treatment reversed SCI-induced increases in Nav1.8 and Nav1.9 currents and reduced the incidence of Nav1.8 resurgent currents, significantly attenuating neuronal hyperexcitability.

Conclusions:

• Nav1.8 sodium channel dysfunction is a critical factor in the hyperexcitability of nociceptive neurons after SCI.
• The interaction between fibroblast growth factor homologous factors (FHFs) and the C-terminal domains of Nav1.8/Nav1.9 represents a viable therapeutic target.
• Targeting FHF modulation of sodium channels offers a promising strategy for managing SCI-associated neuropathic pain.