Prolonged high frequency electrical stimulation (RS) was found to precipitate motor axon degeneration in P0+/− mice, a model of demyelinating Charcot-Marie-Tooth disease (CMT1B). We hypothesized that this was due to the associated changes in voltage-gated Na + channel (VGSC) isoforms with ectopic expression of NaV1.8 on motor axons. The aim of this study was to investigate whether the increased RS toxicity in P0+/− can be attenuated by both the non-selective VGSC blocker lamotrigine and by a novel NaV1.8 subtype selective blocker (Compound 31, Bioorg. Med. Chem. Lett. 2010, 20, 6812; AbbVie Inc.). Investigations were carried out in 1-year-old WT, P0+/− and NaV1.8 knockouts (P0+/−SNS) mice. Tibial nerve RS was carried out under anesthesia using interrupted trains of 200 Hz for 3 hours, which is not neurotoxic in WT. Nerve function was monitored by conventional conduction studies and nerve excitability measures by threshold-tracking. Electrophysiological and histological outcome measures were compared at 3 days after RS to allow for axonal degeneration to occur. Following RS, the CMAP amplitude of P0+/− remained reduced to 50% in association with signs of ongoing axonal degeneration. This toxicity of RS in P0+/− could be largely attenuated by pretreatment with lamotrigine. Furthermore, a similar attenuation was observed in P0+/− following pre-treatment with Compound 31 as well as in P0+/− SNS. Our data suggest that increased toxicity of RS on motor axons in P0+/− could be attributed to an increased activity-dependent Na+ influx, especially through NaV1.8. This raises hope that subtype-selective VGSC blockers could be neuroprotective for motor function in CMT1B.