A new potential target in the treatment of respiratory disease

Mrinalini Dey, Murray Edwards College, New Hall, University of Cambridge, Cambridge CB3 0DF

Airway diseases such as asthma and chronic obstructive pulmonary disorder (COPD) are characterised by airway hyper-responsiveness (AHR), respiratory cough, and dyspnoea. Transient receptor potential vanilloid 1 (TRPV1) is highly expressed by sensory neurons and vagal afferents innervating the airways, and is thought to contribute to the features of airway diseases. Since TRPV1-sensitive nerves may play a role in AHR and bronchoconstriction, there has been much interest in pharmacological therapy which targets TRPV1, in order to treat various respiratory diseases.

A study published by Delescluse et al. [1] in the British Journal of Pharmacology used guinea pig models to investigate the effect of TRPV1 antagonists (SB-705498 and PF-04065463), as well as other pharmacological agents, on AHR, specifically to histamine release induced by ovalbumin (OA). The TRPV1 antagonists used have previously been studied in various models of pain and hyperalgesia but not with regards to their effects in airways. The unanaesthetised guinea pigs were restrained in a double chamber plethysmograph, and the specific airway conductance was calculated from airflow. The classical agents, cetirizine and salbutamol, were found to inhibit OA-induced bronchoconstriction, while atropine, SB-705498 and PF-04065463 greatly inhibited OA-induced AHR to histamine in the guinea pig models. Crucially, this inhibition was not due to antagonism of histamine activity, suggesting that TRPV1 receptors on sensory nerves in the airways may play a significant role in the development of AHR.

Up until now, TRPV1- receptor activity has only been investigated as a potential pharmacological target for the modulation of pain. It has long been known that OA-induced bronchoconstriction in OA-sensitised guinea pigs produces an airway response to allergen similar to that seen in humans, including AHR. AHR, airway inflammation and cough may be due to sensitisation of the sensory nerves in the airways; this new research, along with existing evidence for the role of TRPV1 channels in cough, strongly suggests that TRPV1 antagonists may prove useful in treating AHR in respiratory disease.

References: 

1. Delescluse I, Mace H, Adcock JJ. Inhibition of airway hyper-responsiveness by TRPV1 antagonists (SB-705498 and PF-04065463) in the unanaesthetized, ovalbuminsensitized guinea pig. British Journal of Pharmacology 2012. 166:1822-1832. DOI: 10.1111/j.1476-5381.2012.01891.x

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