Contusive spinal cord injury causes Nav1.8 dysfunction to upregulate small sensory neuron excitability
Abstract
Chronic neuropathic pain associated with spinal cord injury (SCI) poses a significant medical challenge. Studies have shown that moderate thoracic (T10) SCI can substantially enhance the excitability of small diameter dorsal root ganglion (DRG) neurons, suggesting that pain resulting from SCI may arise from pathological alternations in peripheral neurons. However, the molecular mechanisms underlying these changes remain unclear. Here we show that contusive SCI significantly increases transient and resurgent sodium currents mainly through Nav1.8 in rat small DRG neurons. Additionally, SCI increases the proportion of small DRG neurons that produce tetrodotoxin-resistant resurgent currents. The SCI-induced increase of Nav1.8 currents can be reversed by ZL0177, a small peptidomimetic of the critical residues in fibroblast growth factor homologous factors 4 (FHF4) that binds to the C-terminal tail of sodium channels. ZL0177 not only decreases the transient and resurgent currents of Nav1.8 and Nav1.9 but also reduces the proportion of the neurons that generate Nav1.8 resurgent currents. We further show that ZL0177 greatly attenuates the hyperexcitability of small DRG neurons induced by SCI. Taken together, our results indicate Nav1.8 dysfunction following SCI plays a critical role in enhancing excitability of nociceptive neurons. Furthermore, the binding site of FHFs at the C-terminal tail of Nav1.8 and Nav1.9 can serve as a promising therapeutic target for the treatment of SCI…
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