TRPM8-mediated inhibition of pain and itch

Cooling and menthol are sensory stimuli that have been used to treat itch and pain for centuries. However, the downstream mediators of these therapeutic effects are still not clear. The somatosensory nervous system detects thermal, chemical, and mechanical changes in its environment using stimulus specific molecular sensors and cellular pathways. These pathways interact with each other at the spinal cord, thus allowing one stimulus modality to modulate the perception of others. The transient receptor potential (TRP) ion channel TRPM8 is a molecular sensor for cold and cold-mimetic compounds like menthol and icilin. This channel is located on C and Aδ fiber primary sensory neurons that represent a cold-sensing pathway. Therefore, TRPM8 and TRPM8 expressing neurons may be mediating the analgesic and anti-pruritic effects of cooling and menthol. Here, I have detailed experiments using wildtype, trpm8-/- and TRPM8-neuron ablated mice that test this hypothesis. I found that mild cooling inhibits mechanical and heat pain in mouse models of inflammation (CFA) and neuropathy (CCI), but noxious cold temperatures were not analgesic. TRPM8-channels mediated the analgesic effects of cooling on neuropathic pain, but they also mediated cold-hypersensitivity that can be blocked with a TRPM8-antagonist. Selective uptake of the charged lidocaine derivative QX-314 in TRPM8-neurons can also be used to acutely and selectively block cold-pain. Heterologously expressed TRPM8-channels were stimulated in vitro to induce uptake of large dyes and the charged lidocaine derivative QX-314. I have laid the groundwork for using this technique in vivo to acutely silence cold transduction. In addition to pain, responses to multiple puritogens and scratching in the dry skin model of itch were decreased by a range of cold temperatures and menthol. Moreover, I found a role for TRPM8- and TRPM8-neurons in the inhibition of acute itch by cold and cold-mimetics. These experiments have revealed a novel molecular and cellular pathway required for cooling- and cold-mimetic induced analgesia and itch relief. The Knowledge of this pathway has broadened our understanding of how the somatosensory system works, and offers a potential therapeutic target to develop new and improved therapies for itch and pain