Use dependence of peripheral nociceptive conduction in the absence of tetrodotoxin-resistant sodium channel subtypes

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 equipment. Using electrophysiological recordings of single unmyelinated cutaneous fibres and their compound action potential (AP), we evaluated use-dependent changes in mouse peripheral nerves, and the contribution of the tetrodotoxin-resistant (TTXr) sodium channels Na(v)1.8 and Na(v)1.9 to these changes. Nerve fibres were electrically stimulated using single or double pulses at 2Hz. Use-dependent changes of latency, AP amplitude, and duration as well as the fibres' ability to follow the stimulus were evaluated. AP amplitudes substantially diminished in used fibres from C57BL/6 but increased in Na(v)1.8 knockout (KO) mice, with Na(v)1.9 KO in between. Activity-induced latency slowing was in contrast the most pronounced in Na(v)1.8 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(v)1.8 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(V)1.8 KO>Na(V)1.9 KO>wildtype, which is most likely explained by the relative contribution of Na(v)1.7 varying in the same order and the amounts of per-pulse sodium influx expected in the opposite order.