Role of substance P in cough

The sensory neuropeptide, substance P (SP), is present in human airway nerves, beneath and within the epithelium where the condensed localization of neutral endopeptidase (NEP), the major enzyme degrading SP, is observed. To test the hypothesis whether SP stimulates the cough reflex and NEP modifies the cough reflex, we studied the cough response to various stimuli in awake guinea-pigs. Inhibition of NEP with phosphoramidon caused cough, which was inhibited by systemic capsaicin treatment and by aerosols of a specific NK1 receptor antagonist FK 888. Aerosols of FK 888 also inhibited cough induced by bronchoconstricting agents such as acetylcholine and histamine in non-sensitized animals and by ovalbumin antigen in animals sensitized to ovalbumin. The number of coughs induced by histamine aerosols was inhibited by systemic capsaicin treatment and enhanced by pretreatment with a NEP inhibitor phosphoramidon. Likewise, FK 888 inhibited the augmented cough response to aerosolized capsaicin in female guinea-pigs treated with a long-term medication of an angiotensin-converting enzyme inhibitor, cilazapril. In humans, aerosols of SP did not cause cough in normal subjects, whereas it did in patients with common colds. The SP fragment a major metabolite of SP produced by NEP, was less effective compared with SP in these patients, suggesting that damaged epithelium may facilitate the penetration of SP. These findings suggest that SP released from sensory nerves in response to stimuli may mediate cough and NEP may have a role in modulating SP-induced effects.