Group III and IV muscle afferents carry pain and exercise pressor reflex (EPR) signals. However, aberrant signaling of the EPR in patients with cardiovascular disease can increase their risk of a myocardial infarction. Thus, blocking action potentials that signal this reflex could benefit these patients. Immunohistochemistry studies have shown that group III/IV neurons isolated from Sprague Dawley rats express tetrodotoxin-sensitive (TTX-S) voltage-dependent sodium (NaV) channels rNaV1.6 and rNaV1.7, but the contribution of these channels to the TTX-S current is unknown. We initially tested several blockers for selectivity against rNaV1.6 and rNaV1.7 channels expressed in HEK cells and found that µ-conotoxin PIIIA (PIIIA, 500 nM) selectively blocked rNaV1.6 current, while Protoxin II (PTxII, 10 nM) was more selective for rNaV1.7 channels. 4,9-Anhydrotetrodotoxin was found to block non-selectively. To evaluate the TTX-S component currents in muscle afferent neurons, we sequentially added the NaV1.6-selective PIIIA, followed by PTxII to block NaV1.7 current, and then 300 nM TTX to block the remaining TTX-S current. On average PIIIA blocked 14 ± 13% (mean ± SD) and PTxII blocked 70 ± 17% of the TTX-S NaV current in rat muscle afferent neurons. However, the NaV1.6 current fraction significantly varied with cell diameter with mean inhibitions of 0% for neurons < 27 µm, 17% between 27-32 µm (p < 0.05), 5% between 32-27 µm and 21% for neurons > 37 µm (p < 0.05), suggesting differential expression among group III/IV neurons. The TTX-S NaV current in group III/IV neurons is primarily comprised of NaV1.7 >> NaV1.6 = unidentified TTX-S channel activity. Blocking group III/IV action potentials with a selective NaV1.7 channel blocker should inhibit the EPR to reduce the myocardial risk in patients with cardiovascular disease and provide analgesia in patient with severe muscle pain.