Belvisi, MariaBirrell, MarkNasra , JulieJulieNasra2009-08-202009-08-202008http://hdl.handle.net/10044/1/4252Cough is an important protective reflex. Sensory nerve activity mediating cough may be enhanced during disease. Current antitussives possess little clinical efficacy, therefore research is needed to investigate the modulation of airway sensory nerves in order to understand the mechanisms driving chronic cough. A conscious guinea-pig cough model using different tussive stimuli, known to elicit cough in man, was established. Corresponding in vitro effects of these tussive agents on sensory nerve activation were characterised. These agents were also characterised into sub-types as they produced distinct patterns of response. Cigarette smoke (CS) exposure elicited distinct effects on the cough reflex in conscious guinea-pigs and on sensory nerve activity measured in vitro; CS enhanced responses to citric acid (CA), capsaicin (CAPS) and bradykinin, inhibited a prostaglandin E2 (PGE2)-induced response and had no effect on the response to hypertonic saline. The CS model demonstrated neutrophilia and increased mucus in the airways. Focussing on mechanisms driving enhanced cough, revealed that nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF), may play a role in cough reflex sensitisation. An in vitro bioassay confirmed that NGF and BDNF exhibited bioactivity and the anticipated species cross-reactivity. CS exposure augmented the expression of transient receptor potential vanilloid 1 (TRPV1) in vagal sensory nerve ganglion. Pharmacological modulation of guinea-pig and human vagus nerve activation showed that TRPV1 antagonists, capsazepine and SB366791, abolished CAPS-induced depolarisation, partially inhibited low pH, bradykinin and PGE2-induced responses and had no effect on hypertonic saline. Despite positive in vitro and pharmacokinetic analyses, TRPV1 antagonists did not inhibit CAPS-induced cough in vivo. Further work is required to expand upon these findings. This thesis contains an assessment of the effects of sensory nerve modulation in guinea-pig models of cough. Understanding the neural mechanisms associated with this research may help to guide the development of novel antitussive therapies.Thesis or dissertationhttps://doi.org/10.25560/4252