Mice deficient of myelin protein zero (P0) are established models of demyelinating Charcot-Marie-Tooth (CMT) disease. Recent work form our laboratory indicated that in severely affected P0−/− as well as in P0+/− (modeling CMT1B), the neuropathy is aggravated by associated changes in voltage-gated Na + channel isoforms with ectopic expression of NaV1.8 on motor axons. This raised the hypothesis that treatments with NaV1.8 blockers could be used in treatment strategies to improve the motor function in these models. We investigated the effect of the NaV1.8 subtype selective blocker A-803467 and of the novel blocker Compound 31 (C31, Bioorg Med Chem Lett 2010, 20, 6812; AbbVie Inc.) which can be orally administered. Double P0 and NaV1.8 knockouts were used as controls. Multiple measures of tibial nerve excitability by “threshold-tracking” were used to monitor the acute changes in motor axon membrane function up to 2 hours after the blockers. Overall, the baseline excitability measures were much more abnormal in P0−/− at 4 months as compared to P0+/− at 20 months. Nevertheless, in both models, the NaV1.8 blockers produced similar deviations in excitability at a dose of 100 mg/Kg. Most notably, the deviations during both depolarizing and hyperpolarizing threshold electrotonus were increased. Optimizing the parameters of the “Bostock” nodal-internodal myelinated motor axon mathematical model indicated a hyperpolarizing change in resting membrane potential. Our data suggest that ectopic NaV1.8 expression causes a state of motor axon depolarization which can be reversed by pharmacologic NaV1.8 blockers. Measures of axonal excitability could be used to monitor the functional consequence of NaV1.8 blockers in future therapeutic studies.