INTRODUCTION - Targeting TRP Channels for Pain Relief: TRPV1 and Beyond

Abstract

Management of chronic and pathological pain without incurring systemic side effects is a major medical challenge. Currently available drugs, such as non-steroidal antiinflammatory drugs or opioid agonists, are efficacious through peripheral and central mechanisms. However, various complications and development of tolerance are serious problems. Other classes of drugs, such as antidepressants and anti-convulsants, are often used for multiple pain syndromes. However, the efficacy of these drugs is commonly unsatisfactory, and their mechanism of action is not clear. For establishing novel, selective anti-hyperalgesic therapeutic approaches, targeted inhibition of pain-specific pathways or molecules would be ideal, and these approaches suggest straightforward strategies. A new era of exploring such “straightforward” approaches was opened with regard to peripheral nociceptors by the identification of the vanilloid receptor-1 (VR-1), which was designated transient receptor potential channel vanilloid subtype 1 (TRPV1). TRPV1 is a receptor for capsaicin, proton, and noxious heat. Capsaicin has long been known to be a natural compound capable of evoking an intense burning sensation and pain in human and experimental animals. It has been hypothesized that specific manipulation of TRPV1 may selectively relieve pain under injury or inflammatory conditions. Interfering with TRPV1 has been a central focus of these efforts during the 15 years following the cloning of TRPV1. Numerous pharmacological compounds have been developed targeting TRPV1. The characteristics and roles of TRPV1 have been rigorously studied using multiple approaches ranging from biophysical characterization to clinical trials in human subjects. Meanwhile, other members of the TRP channel family in addition to TRPV1 have been suggested to be also involved in nociception under pathophysiological conditions. These studies have identified targets in addition to TRPV1 as potential candidates for selective anti-hyperalgesic treatment free from complications.