Pharmacology of Cough

Cough is the most common respiratory complaint for which medical attention is sought and often presents as the first and most persistent symptom of many respiratory diseases. Treatment options are limited. Despite its importance our understanding of the mechanisms which provoke cough is poor. The respiratory tract is innervated by sensory afferent nerves which are activated by mechanical and chemical stimuli. Activation of capsaicin-sensitive C-fibres and acid-sensitive, capsaicin-insensitive mechanoreceptors innervating the larynx, trachea, and large bronchi regulate the cough reflex. Recently, ion channels of the Transient Receptor Potential (TRP) class such as TRPV1 have been implicated in the afferent sensory loop of the cough reflex and in the heightened cough sensitivity seen in disease. TRPA1 is a Ca²⁺-permeant non-selective channel with 14 ankyrin repeats in its amino terminus which also belongs to the larger TRP family. TRPA1 channels are activated by a range of natural products found in mustard oil, garlic and cannabis and by environmental irritants and is expressed in small diameter, nociceptive neurons. It has been demonstrated that stimulating TRPA1 channels activates vagal broncho-pulmonary C-fibers causing cough both in guinea-pig models and in normal human volunteers. The TRPV4 channel is also widely expressed in mammalian tissues including lung, heart, kidney, sensory neurons. We have preliminary data to suggest that TRPV4 may be present on vagal sensory nerve endings and involved in the activation of lung specific afferents in response to endogenous stimuli such as hypotonicity. Although many exogenous stimuli are known to activate particularly TRPA1 and TRPV1, it is still unknown how cough and other reflexes are elicited in health and disease by endogenous agents, and whether these ion channels are involved.