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

Abstract

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, Nav1.8 and Nav1.9, 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 Nav1.8 and Nav1.9 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 Nav isoform transcript and protein expressed in injured neurons with the exception of the Nav1.9 protein, which exhibited no change, while in contralateral non‑injured neurons, the levels of protein and mRNA remained unchanged. Nav isoform functional analysis was then performed in L(4‑6) DRG neurons 14 days after CCI. The Nav1.8 current density was markedly decreased in injured DRG neurons following CCI. The voltage‑dependent activation of the Nav1.8 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 Nav1.9 was not affected by CCI. The present study demonstrated that ectopic discharge following CCI, which was likely induced by a positive shift in the Nav1.8 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.

Antinociceptive Effects of AGAP, a Recombinant Neurotoxic Polypeptide: Possible Involvement of the Tetrodotoxin-Resistant Sodium Channels in Small Dorsal Root Ganglia Neurons

“…Our results showed that Na V 1.8 mainly expressed in small- and medium-sized DRG neurons that rarely contained NF200, whereas Na V 1.9 selectively expressed in small-sized DRG neurons that completely did not contain NF200. This finding is similar to preliminary reported results (Yu et al, 2011; Li et al, 2015). Therefore, DRG neurons with diameters of 15–25 μm (small-sized) were selected for continued experiments.…”

Inhibition of sodium conductance by cannabigerol contributes to a reduction of dorsal root ganglion neuron excitability

“…If the V 1/2 of each Na v channel is compared with the RMP of the cell where it is predominantly found, a rough estimate of Na v channel inactivation at RMP can be determined. In Figure 8, we show a comparison of 5 general tissue‐specific cell types with RMPs and V 1/2 of their respective predominantly‐expressed Na v channels, which are taken from published data (Amir et al, 1999; Cannon et al, 1993; Espinosa & Kavalali, 2009; Ghovanloo et al, 2020; Ghovanloo et al, 2021; Ghovanloo, Peters, & Ruben, 2018; He & Soderlund, 2014; Howard et al, 2007; Huang et al, 2017; Li et al, 2015; Mason & Cummins, 2020). These comparisons suggest that in the five cell types (other cells and tissue must be taken into consideration on an individual basis) that are shown, Na v 1.7 channels in DRG neurons are the most inactivated of the nine subtypes (Figure 8a–e).…”

Molecular Changes in the Dorsal Root Ganglion during the Late Phase of Peripheral Nerve Injury–induced Pain in Rodents: A Systematic Review

“…23 In contrast, another study, using the same species, breed, and sex, found a decrease of Nav1.9 expression, which was only significant on the mRNA level (table 5). 64 The discrepancy was noticed by the authors, but a potential explanation was unfortunately not given. Another study investigating Nav1.9 on the mRNA level also found Nav1.9 to be decreased at 28 and 90 days after spared nerve injury.…”