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

Abstract

The action potential (AP) initiation in the nerve terminals and AP conduction along the axons do not necessarily depend on the same subtypes of Na_V1s. We evaluated the role of tetrodotoxin(TTX)-sensitive and TTX-resistant Na_V1s 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. Virtually all the jugular neurons expressed the TTX-sensitive channel Na_V1.7 along with TTX-resistant Na_V1.8 and Na_V1.9. Tracheal nodose neurons also expressed Na_V1.7, but less frequently Na_V1.8 and Na_V1.9. Na_V1.6 was expressed in approximately 40% of the jugular and 25% of nodose tracheal neurons. Other Na_V1 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, but was inhibited by Na_V1.8 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. In contrast, both AP initiation and conduction in nodose nociceptors was abolished by TTX or selective Na_V1.7 blockers. Distinctions between the effect of a drug at inhibiting AP in the nerve terminals within the airways vs. at conduction sites along the vagus nerve is relevant to therapeutic strategies involving inhaled Na_V1 blocking drugs.

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