A TRP channel trio mediates acute noxious heat sensing

Acute pain represents a crucial alarm signal to protect us from injury(1). Whereas the nociceptive neurons that convey pain signals were described more than a century ago(2), the molecular sensors that detect noxious thermal or mechanical insults have yet to be fully identified(3-6). Here we show that acute noxious heat sensing in mice depends on a triad of transient receptor potential (TRP) ion channels: TRPM3, TRPV1, and TRPA1. We found that robust somatosensory heat responsiveness at the cellular and behavioural levels is observed only if at least one of these TRP channels is functional. However, combined genetic or pharmacological elimination of all three channels largely and selectively prevents heat responses in both isolated sensory neurons and rapidly firing C and A delta sensory nerve fibres that innervate the skin. Strikingly, Trpv1(-/-)Trpm3(-/-)Trpa1(-/-)triple knockout (TKO) mice lack the acute withdrawal response to noxious heat that is necessary to avoid burn injury, while showing normal nociceptive responses to cold or mechanical stimuli and a preserved preference for moderate temperatures. These findings indicate that the initiation of the acute heat-evoked pain response in sensory nerve endings relies on three functionally redundant TRP channels, representing a fault-tolerant mechanism to avoid burn injury.