Positive shift of Nav1.8 current inactivation curve in injured neurons causes neuropathic pain following chronic constriction injury

Neuropathic pain is a global medical concern, characterized by spontaneous pain, heat hyperalgesia and mechanical allodynia. The condition has been associated with alterations in the voltage-gated sodium channels, Na(v)1.8 and Na(v)1.9, in nociceptive neurons termed nociceptors. However, an explanation for the contribution of these channels to the phenotype observed in neuropathic pain remains to be elucidated. The changes induced by chronic constriction injury (CCI) to Na(v)1.8 and Na(v)1.9 mRNA and protein levels, as well as electrical currents in injured and contralateral non-injured dorsal root ganglion (DRG) neurons are described in the present study. A marked downregulation was observed for each Na-v isoform transcript and protein expressed in injured neurons with the exception of the Na(v)1.9 protein, which exhibited no change, while in contralateral non-injured neurons, the levels of protein and mRNA remained unchanged. Na-v isoform functional analysis was then performed in L4-6 DRG neurons 14 days after CCI. The Na(v)1.8 current density was markedly decreased in injured DRG neurons following CCI. The voltage-dependent activation of the Na(v)1.8 channel in these neurons was shifted to depolarized potentials by 5.3 mV, while it was shifted to hyperpolarized potentials by 10 mV for inactivation. The electrophysiological function of Na(v)1.9 was not affected by CCI. The present study demonstrated that ectopic discharge following CCI, which was likely induced by a positive shift in the Na(v)1.8 current inactivation curve in injured neurons, enhanced the excitability of the neurons by facilitating tetrodotoxin-resistant sodium channels into the fast inactivation state and did not occur as a result of a compensatory redistribution in the contralateral uninjured neurons.