Cough Sensors. III. Opioid and Cannabinoid Receptors on Vagal Sensory Nerves

Abstract

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.

Targeting peripheral afferent nerve terminals for cough and dyspnea

“…GPCRs may also serve to inhibit excitability of vagal afferent nerves to decrease generator potential amplitude in response to an activating stimulus. An example of this may be found in the nociceptive receptor NOP1, as well as certain opioid and cannabinoid receptors [20] [21]. …”

Central regulation of the cough reflex: Therapeutic implications

“…Autacoids such as adenosine, PGE2 and epinephrine also prevent neuropeptide release but activate or increase airway C-fibre excitability [59,85-89]. Surprisingly, there have been no published studies evaluating the ability of drugs such as codeine, dextromethorphan, baclofen, nociceptin or cannabanoid CB2 receptor agonists to prevent airway afferent nerve discharge despite evidence that they act peripherally to limit coughing [16,58,68,76,77,90,91]. Undem and colleagues have found no evidence for a direct inhibition of vagal afferent discharge (C- or A∂-fibres) in guinea pigs by delta-opioid receptor agonists, nociceptin or CB2 receptor agonists (Undem, personal communication).…”

In vivo anti-tussive activity and structural features of a polysaccharide fraction from water extracted Withania somnifera

“…Codeine and dextromethorphan are extensively used for the treatment of cough (Chung, 2009). But current anti-tussives, such as opiods, have unwanted side-effects (Belvisi and Hele, 2009 Withania somnifera popularly known as Ashwagandha is a plant in Solanaceae family. Native to India, this small evergreen shrub is commonly cultivated in the tropics and has been used in traditional Indian medicine for more than 2000 years (Kulkarni and Dhir, 2008).…”