Purinergic Receptors as Emerging Targets in the Management of Chronic Cough: From Pathophysiology to Clinical Application

Chronic cough is a prevalent and debilitating condition that significantly impairs quality of life and remains a therapeutic challenge owing to the limited efficacy and unfavorable adverse effect profiles of existing treatments. In recent years, a deeper understanding of the neurobiology of the cough reflex has unveiled the pivotal role of purinergic signaling in the pathophysiology of cough hypersensitivity. Extracellular adenosine triphosphate, released in response to airway inflammation and irritation, activates the P2X3 and P2X2/3 receptors on vagal sensory nerves, triggering and sensitizing the cough reflex. This has led to the emergence of P2X3 receptor antagonists as a promising new class of targeted therapies. This comprehensive review of the pathophysiology of chronic cough focuses on the role of purinergic signaling, with an examination of the preclinical and clinical evidence supporting the efficacy of P2X3 antagonists, such as gefapixant, in reducing cough frequency. Furthermore, we discuss the clinical and safety considerations of these novel drugs, including the main challenge of taste-related adverse effects, and explore future perspectives, such as the development of more selective molecules and the identification of biomarkers to guide personalized treatment strategies. The advent of purinergic receptor modulation marks a significant milestone in the management of chronic cough, offering new hope for patients with this refractory condition.