Therapeutic strategies that target vagal C-fibre terminals for the treatment of chronic cough

Activation of vagal C-fibres causes coughing in both animals and humans. In chronic pathological cough, these fibres become hypersensitive, responding to stimuli that are normally undetectable. A rational approach to normalise the hypersensitivity would be to target mechanisms that diminish C-fibre activation. Airway C-fibres are stimulated by inhaled irritants and endogenous substances such as inflammatory mediators and acids. These stimuli interact with receptors or ion channels on nerve terminals, causing depolarisation of the resting membrane potential, known as the generator potential. If this depolarisation is large and fast enough, voltage-gated sodium (Na_V) channels activate, generating action potentials that transmit signals to the CNS. To counteract this process, three general pharmacological strategies can be pursued at the C-fibre terminals, primarily located in the airway mucosa: 1) blocking the interaction between stimuli and receptors/ion channels, 2) modulating ion channels to reduce generator potential amplitude, and 3) inhibiting specific Na_V channel subtypes responsible for action potential initiation and conduction.