Ozone-Induced Hypertussive Responses in Rabbits and Guinea Pigs

Abstract

Cough remains a major unmet clinical need, and preclinical animal models are not predictive for new antitussive agents. We have investigated the mechanisms and pharmacological sensitivity of ozone-induced hypertussive responses in rabbits and guinea pigs. Ozone induced a significant increase in cough frequency and a decrease in time to first cough to inhaled citric acid in both conscious guinea pigs and rabbits. This response was inhibited by the established antitussive drugs codeine and levodropropizine. In contrast to the guinea pig, hypertussive responses in the rabbit were not inhibited by bronchodilator drugs (β2 agonists or muscarinic receptor antagonists), suggesting that the observed hypertussive state was not secondary to bronchoconstriction in this species. The ozone-induced hypertussive response in the rabbit was inhibited by chronic pretreatment with capsaicin, suggestive of a sensitization of airway sensory nerve fibers. However, we could find no evidence for a role of TRPA1 in this response, suggesting that ozone was not sensitizing airway sensory nerves via activation of this receptor. Whereas the ozone-induced hypertussive response was accompanied by a significant influx of neutrophils into the airway, the hypertussive response was not inhibited by the anti-inflammatory phosphodiesterase 4 inhibitor roflumilast at a dose that clearly exhibited anti-inflammatory activity. In summary, our results suggest that ozone-induced hypertussive responses to citric acid may provide a useful model for the investigation of novel drugs for the treatment of cough, but some important differences were noted between the two species with respect to sensitivity to bronchodilator drugs.

Downregulation of the cough reflex by aclidinium and tiotropium in awake and anesthetized rabbits

“…Apart from the study by Birrell et al [17] on guinea pigs, there are a few other investigations on the antitussive effects of tiotropium both in animal species [44] and patients [12,13,16,18,19]. Recently, at variance with previous and present results, a lack of tiotropium antitussive effects on ozone-induced hypertussive responses in rabbits has been reported [7]. The reasons of the discrepancy with our results are not clear, but could be tentatively attributed to differences in the experimental conditions.…”

“…More recently, it has been shown that inhaled tiotropium attenuates after 1 h cough induced by capsaicin in the guinea pig and that this effect is mediated by TRPV1 receptors through a mechanism unrelated to its anticholinergic activity [17]. However, Clay et al [7] have reported that, in contrast to the guinea pig, the ozone-induced hypertussive responses to citric acid are not inhibited by tiotropium in the rabbit.…”

“…Note the complete suppression of the cough reflex in some preparations. of studies carried out on animal models could not be predictive for new antitussive agents [6,7]. Nevertheless, we are confident that investigations performed on healthy preparations can provide useful insights into the regulation of the cough reflex as well as hints for further studies on this reflex and possibly for the development of novel antitussive strategies.…”

“…In the final solution, the concentration of DMSO was less than 5%. Tiotropium bromide monohydrate (SigmaAldrich) was dissolved in 0.9% NaCl solution at the desired concentrations [7,33]. All drugs were freshly prepared on the day of administration.…”

An update and systematic review on drug therapies for the treatment of refractory chronic cough

“…Further, rats and mice do not cough and guinea pigs while being the preferred cough animal model have features driving cough that may not be critical in humans [54]. Few attempts have been made to generate models displaying the features of CHS [83] or the urge to cough [84], which likely drives behavioral coughing. When specific efforts are made disease-specific neurophenotypes can be encapsulated in animal models and have shown consistent outcomes with human phenotypes [82].…”