Na_V1.9 channels in muscle afferent neurons and axons

The exercise pressor reflex (EPR) is activated by muscle contractions to increase heart rate and blood pressure during exercise. While this reflex is beneficial in healthy individuals, the reflex activity is exaggerated in patients with cardiovascular disease, which is associated with increased mortality. Group III and IV afferents mediate the EPR and have been shown to express both tetrodotoxin-sensitive (TTX-S, Na_V1.6, and Na_V1.7) and -resistant (TTX-R, Na_V1.8, and Na_V1.9) voltage-gated sodium (Na_V) channels, but Na_V1.9 current has not yet been demonstrated. Using a F^--containing internal solution, we found a Na_V current in muscle afferent neurons that activates at around -70 mV with slow activation and inactivation kinetics, as expected from Na_V1.9 current. However, this current ran down with time, which resulted, at least in part, from increased steady-state inactivation since it was slowed by both holding potential hyperpolarization and a depolarized shift of the gating properties. We further show that, following Na_V1.9 current rundown (internal F^-), application of the Na_V1.8 channel blocker A803467 inhibited significantly more TTX-R current than we had previously observed (internal Cl^-), which suggests that Na_V1.9 current did not rundown with that internal solution. Using immunohistochemistry, we found that the majority of group IV somata and axons were Na_V1.9 positive. The majority of small diameter myelinated afferent somata (putative group III) were also Na_V1.9 positive, but myelinated muscle afferent axons were rarely labeled. The presence of Na_V1.9 channels in muscle afferents supports a role for these channels in activation and maintenance of the EPR. NEW & NOTEWORTHY Small diameter muscle afferents signal pain and muscle activity levels. The muscle activity signals drive the cardiovascular system to increase muscle blood flow, but these signals can become exaggerated in cardiovascular disease to exacerbate cardiac damage. The voltage-dependent sodium channel Na_V1.9 plays a unique role in controlling afferent excitability. We show that Na_V1.9 channels are expressed in muscle afferents, which supports these channels as a target for drug development to control hyperactivity of these neurons.