Pharmacological targeting of the heat-activated TRP channel triad for pain relief

About 1 in 5 adults worldwide suffer from moderate-to-severe chronic pain. Existing pain therapies are often insufficient to obtain sufficient relief. Moreover, widely used analgesic drugs have serious side-effects and, as is the case with opioids, cause tolerance and potentially fatal addiction. Therefore, there is a large unmet need for new and safer pain therapies. In this project, we focus on a triad of ion channels, TRPV1, TRPM3 and TRPA1, which we recently identified as the essential molecular sensors of burning pain in sensory neurons. In animal studies, pharmacological inhibition of these channels results in significant pain relief in a variety of models of persistent pain. Unfortunately, clinical development of antagonists of these channels is hampered by a poor understanding of their in vivo action with respect to pain relief and unwanted side-effects (including increased body core temperature and insensitivity to noxious heat). We hypothesize that the in vivo effects of specific antagonists are dictated by (1) the molecular mechanisms whereby they modulate the opening and closing of the TRP channels, and (2) how they modulate the interplay between the members of the triad. To investigate this, we propose a multifaceted approach, including cellular electrophysiology, biophysical modeling and in vivo pain assays in wild type and TRP channel-deficient mice. We anticipate that this project will accelerate the rational development of novel analgesic drugs.