Rationale: Chronic cough (cough >8 weeks) is common, leads to an impaired quality of life, and is difficult to treat. Despite intensive investigation, ~40% of patients referred to a specialist cough clinic will remain resistant to treatment targeted at peripheral triggers such as reflux disease, rhino-sinusitis or airways inflammation. An improved understanding of underlying mechanisms in such patients would facilitate drug development. I propose that there are several important similarities between pain and cough that can be exploited better to understand underlying mechanisms. In chronic pain, a long-lasting up-regulation of afferent pain processing may be generated by changes within the central nervous system, mediated by the NMDA receptor and/or by impaired inhibitory mechanisms. A similar central neuronal up-regulation of cough may also be responsible for the pathogenesis of chronic cough (CC). Methods: A series of experimental studies were performed to address this hypothesis. Firstly, the anti-tussive and analgesic effect of ketamine, an NMDA receptor antagonist, was investigated in CC patients and healthy controls (HC). Pain thresholds were measured using electrical stimulation in the oesophagus, pharynx and chest wall. Cough sensitivity was measured using standard capsaicin cough challenges. Secondly, I designed and tested novel capsaicin cough challenges in CC patients, asthmatics (A) and HC. ED50 (dose inducing and least 50% maximal cough frequency) and Cmax (maximal cough frequency) was compared by group and gender. Finally, I investigated 2 independent mechanisms of cough inhibition. Results:(i) CC patients, but not HC, had cough induced by oesophageal electrical stimulation, whilst pain thresholds were similar. Ketamine had a significant analgesic effect but no antitussive effect in CC or HC.(ii) CC patients had both cough hypersensitivity (lower ED50) and cough hyper-responsiveness (higher Cmax) on full capsaicin dose-response curves. (iii) Both a painful cold stimulus applied to the hand and conscious cough suppression significantly inhibited capsaicin-induced cough responses in CC and HC.Conclusions:CC patients exhibited increased oesophageal sensitivity to cough, but not pain, providing evidence for a process of central sensitisation in the brainstem. Higher capsaicin-induced cough frequencies in CC may also be mediated by an increased gain within the CNS, possibly because of failed tonic inhibitory mechanisms. Furthermore, CC patients may have poorer conscious control of coughing. In conclusion, an improved understanding of mechanisms in cough will provide a strong scientific rationale for the development of novel therapeutics.