Different role of TTX‐sensitive voltage‐gated sodium channel (NaV1) subtypes in action potential initiation and conduction in vagal airway nociceptors.

Key points: The action potential initiation in the nerve terminals and its subsequent conduction along the axons of afferent nerves are not necessarily dependent on the same voltage‐gated sodium channel (NaV1) subunits. The action potential initiation in jugular C‐fibres within airway tissues is not blocked by TTX; nonetheless, conduction of action potentials along the vagal axons of these nerves is often dependent on TTX‐sensitive channels. This is not the case for nodose airway Aδ‐fibres and C‐fibres, where both action potential initiation and conduction is abolished by TTX or selective NaV1.7 blockers. The difference between the initiation of action potentials within the airways <italic>vs</italic>. conduction along the axons should be considered when developing NaV1 blocking drugs for topical application to the respiratory tract. Abstract: The action potential (AP) initiation in the nerve terminals and its subsequent AP conduction along the axons do not necessarily depend on the same subtypes of voltage‐gated sodium channels (NaV1s). We evaluated the role of TTX‐sensitive and TTX‐resistant NaV1s in vagal afferent nociceptor nerves derived from jugular and nodose ganglia innervating the respiratory system. Single cell RT‐PCR was performed on vagal afferent neurons retrogradely labelled from the guinea pig trachea. Almost all of the jugular neurons expressed the TTX‐sensitive channel NaV1.7 along with TTX‐resistant NaV1.8 and NaV1.9. Tracheal nodose neurons also expressed NaV1.7 but, less frequently, NaV1.8 and NaV1.9. NaV1.6 were expressed in ∼40% of the jugular and 25% of nodose tracheal neurons. Other NaV1 α subunits were only rarely expressed. Single fibre recordings were made from the vagal nodose and jugular nerve fibres innervating the trachea or lung in the isolated perfused vagally‐innervated preparations that allowed for selective drug delivery to the nerve terminal compartment (AP initiation) or to the desheathed vagus nerve (AP conduction). AP initiation in jugular C‐fibres was unaffected by TTX, although it was inhibited by NaV1.8 blocker (PF‐01247324) and abolished by combination of TTX and PF‐01247324. However, AP conduction in the majority of jugular C‐fibres was abolished by TTX. By contrast, both AP initiation and conduction in nodose nociceptors was abolished by TTX or selective NaV1.7 blockers. Distinction between the effect of a drug with respect to inhibiting AP in the nerve terminals within the airways <italic>vs</italic>. at conduction sites along the vagus nerve is relevant to therapeutic strategies involving inhaled NaV1 blocking drugs. [ABSTRACT FROM AUTHOR]