Drug design and development through the vanilloid receptor

The vanilloid receptor (TRPV1) has attracted a great expectation in pain therapeutics for the treatment of chronic inflammatory conditions. As a result, several drug discovery programmes were launched in the past years that yielded a large number of receptor agonists and antagonists. However, despite the claimed therapeutic potential of TRPV1 modulators, a disappointing number of candidates have progressed into clinical trials and those were only for dental pain and migraine, indicating that our understanding of the role of TRPV1 in pain is still very limited. The widespread distribution of TRPV1 in different tissues suggests an involvement in body functions other than pain. Indeed, new findings indicate that TRPV1 is tonically active in physiological conditions and its pharmacological blockade leads to hyperthermia. Furthermore, the full abrogation of TRPV1 in some models of chronic pain results in enhanced pain. Therefore, a remaining challenge is the development of drugs that preserve the physiological activity of TRPV1 and downregulate the function of overactive receptors.