Chronic pruritus: From pathophysiology to drug design

Pruritus, the most common symptom in dermatology, is an innate response capable of protecting skin against irritants. Nonetheless, when it lasts more than six weeks it is assumed to be a chronic pathology having a negative impact on people's lives. Chronic pruritus (CP) can occur in common and rare skin diseases, having a high prevalence in global population. The existing therapies are unable to counteract CP or are associated with adverse effects, so the development of effective treatments is a pressing issue. The pathophysiological mechanisms underlying CP are not yet completely dissected but, based on current knowledge, involve a wide range of receptors, namely neurokinin 1 receptor (NK1R), Janus kinase (JAK), and transient receptor potential (TRP) ion channels, especially transient receptor potential vanilloid 1 (TRPV1) and transient receptor potential ankyrin 1 (TRPA1). This review will address the relevance of these molecular targets for the treatment of CP and molecules capable of modulating these receptors that have already been studied clinically or have the potential to possibly alleviate this pathology. According to scientific and clinical literature, there is an increase in the expression of these molecular targets in the lesioned skin of patients experiencing CP when compared with non-lesioned skin, highlighting their importance for the development of potential efficacious drugs through the design of antagonists/inhibitors.