A physiological model of the human cough reflex : investigations of the afferent pathway and antitussive studies
Cough is a common symptom of respiratory disease. Assessment of antitussives has relied mainly on animal studies and clinical trials in which recording of natural cough is difficult. This thesis describes the use of ultrasonically nebulized distilled water (UNOW) to induce cough in man. Investigation of the chemosensitivity of this response identified that extremes of pH, a chloride concentration below 75mmol/l, but not changes in osmolarity induce cough which reflects afferent rapidly adapting recep~or sensitivity in animal studies. Inhaled beta-adrenergic and anticholinergic bronchodilators, which inhibit cough in asthma, markedly reduced UNOW-induced cough in both healthy and asthmatic volunteers. Bronchoconstriction with inhaled leukotriene 04, which constricts both asthmatic and non-asthmatic airways, also caused coughing. Inhibition of bronchoconstriction either specifically or non-specifically resulted in inhibition of cough. Nedocromil sodium and the diuretic, frusemide, but not the commonly prescribed opiate, codeine, exhibited antitussive activity. Cough was also induced by inhalation of the C-fibre stimulants, capsaicin and prostaglandin E2 (PGE2), which was characterised by studies of adaptation, cross-adaptation and antitussives. UNOW and PGE2, but not capsaicin, exhibited rapid adaptation of cough. Crossadaptation, however, did not occur suggesting distinct mechanisms of cough mediation. Nedocromil inhibited capsaicin-induced cough but not PGE2-induced cough, while fenoterol did not affect either challenge. Oxitropium, which inhibited UNOW-induced cough, did not reduce cough associated with upper respiratory tract infection. Cough can be induced by a variety of inhaled stimuli. These can identify differences in response which may signal a number of pathways leading to cough. Antitussive activity may also be specific to individual challenges. This diversity in response reflects the complex neurological organisation of cough and may be related to pathological causes of cough.