Targeting Thermo-TRP Channels for Pain and Itch Relief

Transient Receptor Potential (TRP) channels are multifunctional sensory proteins that are abundant in the skin and involved in the sensory pathways of pain, itch, and inflammation. Identified temperature-sensitive representatives of TRP or thermo-TRP channels belong to four subfamilies and include both heat- and cold-sensitive channels. Most of these thermo-TRP channels are molecular sensors of chemical and mechanical noxious stimuli that evoke pain and itch sensations. Thermo-TRP channels are crucial for physiological functions, as they constantly monitor internal body temperature and external thermal ambient hazards associated with heat and cold. In addition to temperature, thermo-TRPs exhibit remarkable sensitivity to a wide range of pungent compounds commonly present in food. In particular, allicin, capsaicin, chloroquine, cinnamon aldehyde, horseradish, menthol, mustard oil, piperine, wasabi, and others. All thermo-TRPs discovered to date belong to four channel subfamilies: ankyrin (TRPA1), canonical (TRPC5), melastatin (TRPM2-5, TRPM8), and vanilloid (TRPV1-4), each having distinct structural architecture and membrane topology. Whereas these channels are critical for temperature sensing, they also play important roles in pain perception under normal conditions and aberrant responses in pathological pain states, thus making them a robust target for the development of new analgesics. In addition to pain, various thermo- and other TRP channels are key transducers of itch sensation, coupling with pruriceptors and converting external stimuli into sensory neuronal signals. Other receptors, including G protein-coupled receptors (GPCRs) and protease-activated receptors (PARs), have been identified as critical in transducing noxious and itchy stimuli into action potentials that are conducted over primary afferent fibers into the central nervous system (CNS). Two sensations, such as pain and itch, share many similarities, including common sensory neurons, mediators, and receptors involved in peripheral and central neuronal sensitization and synaptic transmission in the CNS. However, there are distinct differences in the molecular mechanisms governing itch and pain in skin pathologies. Ubiquitous expression of TRP channels underscores their relevance across virtually every facet of human physiology and pathology. They remain viable and promise targets for the development of novel therapeutics to treat acute and chronic pain and itch, inflammation, and various diseases.