Voltage-dependent sodium (Na(V)) channels in group IV sensory afferents

Patients with intermittent claudication suffer from both muscle pain and an exacerbated exercise pressor reflex. Excitability of the group III and group IV afferent fibers mediating these functions is controlled in part by voltage-dependent sodium (Na(V)) channels. We previously found tetrodotoxin-resistant Na(V)1.8 channels to be the primary type in muscle afferent somata. However, action potentials in group III and IV afferent axons are blocked by TTX, supporting a minimal role of Na(V)1.8 channels. To address these apparent differences in Na(V) channel expression between axon and soma, we used immunohistochemistry to identify the Na(V) channels expressed in group IV axons within the gastrocnemius muscle and the dorsal root ganglia sections. Positive labeling by an antibody against the neurofilament protein peripherin was used to identify group IV neurons and axons. We show that >67% of group IV fibers express Na(V)1.8, Na(V)1.6, or Na(V)1.7. Interestingly, expression of Na(V)1.8 channels in group IV somata was significantly higher than in the fibers, whereas there were no significant differences for either Na(V)1.6 or Na(V)1.7. When combined with previous work, our results suggest that Na(V)1.8 channels are expressed in most group IV axons, but that, under normal conditions, Na(V)1.6 and/or Na(V)1.7 play a more important role in action potential generation to signal muscle pain and the exercise pressor reflex.