Coughing is a principal symptom of COPD and patients demonstrate an increased cough response to inhaled capsaicin or citric acid (Doherty et al. 2000). Tobacco smoke (TS) is known to cause COPD and previous work demonstrates enhanced cough following 2 weeks TS exposure in guinea-pigs (Karlsson et al. 1991). The aim of our studies was to further investigate the time-course of the enhanced model and evaluate the preliminary effects of codeine and terbutaline.Male Dunkin-Hartley guinea-pigs (350-550 g, Harlan UK,) were exposed to either air or TS generated by 5 research cigarettes, (CS, 2R4F; University of Kentucky, USA), for a 3 sec puff every 30 sec, for 1, 2, 3, 5 or 10 days. At 1 or 5 h after TS exposure or 24 h after 1, 2, 3, 5 or 10 days exposure conscious, unrestrained animals were placed in a plethysmograph chamber (Buxco, USA) and challenged with an aerosol of 0.3 M citric acid (CA, in 0.9 % saline) for 10 min. Cough and Penh AUC (measure of bronchoconstriction) were recorded during the 10 min exposure and for a further 10 min after exposure (El-Hashim et al. 2003). In a 2nd series of experiments, a TS response was performed using the 2 day exposure regime with 1-5 CS. Cough response to CA was evaluated at 24 h after the last TS or air exposure. To evaluate the effects of compounds, animals were exposed to 4 CS or air for 2 days and challenged with CA 24 h after the last exposure. Codeine (60 mg kg^-1, p.o., -30 min), terbutaline (1 or 3 mg kg^-1, s.c., -1 h) or vehicle (carboxymethylcellulose 0.4 % or saline, respectively) were dosed prior to CA challenge. Data are expressed as mean ± s.e.mean and significance was defined as p < 0.05 (Mann Whitney Rank sum test).

Following 1-5 CS or 1, 2, 3, 5 and 10 day TS exposure a significant increase in the cough response to 0.3 M CA was observed at 24 h after the last exposure, with no effect on Penh (Table 1). No enhanced response was observed at 1 or 5 h following 1 day TS. Codeine significantly inhibited TS enhanced cough and Penh by 53±13 and 75±7 %, respectively. Terbutaline inhibited cough by 15±17 and 61±19 % and Penh by 10±21 and 83±6 % for 1 and 3 mg kg^-1, respectively, reaching significance at 3 mg kg^-1.

Table 1. CS-response and time-course of enhanced cough and Penh to CA exposure. Data are presented as mean ± s.e.mean for the total 20 min response and * denotes significant increase from air time-matched controls. N = 10 per group.

TS exposure results in an enhanced cough response to citric acid in guinea-pigs from as early as 1 day TS exposure and using as little as 1 CS exposure. Desensitization of the response was observed at 1 and 5 h after TS exposure. Penh measurements in these studies quantify the observations by Karlsson et al. (1991) of no enhanced bronchoconstriction. Clinically relevant compounds inhibit enhanced cough and baseline constriction, suggesting the model is useful for testing potential new therapies. Factors which may contribute to the enhancement other than bronchoconstriction e.g. inflammation and mucus secretion are under further investigation.

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