Cough sensors. III. Opioid and cannabinoid receptors on vagal sensory nerves

Cough is a persistent symptom of many inflammatory airways' diseases. Cough is mediated by receptors sited on sensory nerves and then through vagal afferent pathways, which terminate in the brainstem respiratory centre. Cough is often described as an unmet clinical need. Opioids are the only prescription-based antitussives currently available in the UK. They possess limited efficacy and exhibit serious unwanted side effects, such as physical dependence, sedation, respiratory depression and gastrointestinal symptoms. There are three classical opioid receptors: the mu, kappa and delta receptors. Peripheral opioid receptors are sited on sensory nerves innervating the airways. A greater understanding of the role of the peripheral and centrally sited opioid receptors is necessary to allow the development of targeted treatments for cough. Because of the limited efficacy and the side-effect profile of the opioids, potential new treatments are sought to alleviate cough. One class of compounds that is currently under examination is the cannabinoids. Like the opioids, cannabinoids have peripheral and centrally sited receptors and also suffer from the blight of unwanted centrally mediated side effects such as sedation, cognitive dysfunction, tachycardia and psychotropic effects. Two cannabinoid receptors have been identified, the CB(1) and CB(2) receptors, and their distribution varies throughout the peripheral and central nervous system. Encouragingly, early studies with these compounds suggest that it may be possible to separate their antitussive activity from their centrally mediated side effects, with CB(2) agonists showing potential as putative new treatments for cough. In this chapter, we describe the opioid and cannabinoid receptors, their distribution and the effects they mediate. Moreover, we highlight their potential advantages and disadvantages in the treatment of cough.