Use dependence of peripheral nociceptive conduction in the absence of TTXr sodium channel subtypes

Key points

• This study examines conduction in peripheral nerves and its use dependence in TTXr sodium channel (Na_v1.8, Na_v1.9) knock out and wildtype animals.
• We observed use-dependent decrease of single fibres' and compound action potential's amplitude in peripheral mouse C-fibres (wildtype). This matches the previously published hypothesis that increased Na/K-pump activity is not the underlying mechanism for use dependent changes of neural conduction.
• Knocking out TTXr sodium channels influences use dependent changes of conductive properties (AP-amplitude, latency, conduction safety) in the order Na_v1.8 KO >  Na_v1.9KO >  wildtype.
• This is most likely explained by different subsets of presumably (relatively) Na_v1.7-rich conducting fibres in KO animals as compared to wild types, in combination with reduced per-pulse sodium influx.

Abstract

Use dependency of peripheral nerves, especially of nociceptors correlates with receptive properties. Slow inactivation of voltage gated sodium channels has been discussed to be the underlying mechanism – pointing to a receptive class related difference of sodium channel equipage. Using electrophysiological recordings of single unmyelinated (C) cutaneous fibres and their compound action potential (CAP), we evaluated use dependent changes in mouse peripheral nerves, and the contribution of the TTXr sodium channels Na_v1.8 and Na_v1.9 to these changes. Nerve fibres were electrically stimulated using single or double pulses at 2 Hz. Use dependent changes of latency, action potential (AP) amplitude, and duration as well as fibres' ability to follow the stimulus were evaluated. AP amplitudes substantially diminished in used fibres from C57BL/6 but increased in Na_v1.8 KO mice, with Na_v1.9 KO in between. Activity induced latency slowing was in contrast the most pronounced in Na_v1.8 KOs and the least in wildtype mice. The genotype was also predictive of how long fibres could follow the double pulsed stimulus with wildtype fibres blocking first and Na_v1.8 KO fibres enduring the longest. In contrast, changes in spike duration were less pronounced and displayed no significant tendency. Thus, all major measures of peripheral nerve accommodation (amplitude, latency and durability) depended on genotype. All use dependent changes appeared in the order Na_V1.8 KO >  Na_V1.9 KO >  wildtype, which is most likely explained by the relative contribution of Na_v1.7 varying in the same order and the amounts of per-pulse-sodium influx expected in the opposite order.

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