Cold comfort pharm.

Cooling of the skin has long been thought to be beneficial in pain states but intense cold is clearly noxious. Does cooling lead to pain or gain? Rapid progress in this controversy has been made since the discovery of specific ion channels of the transient receptor potential (TRP) family that are activated by cooling of sensory nerve cells to below body temperature. This review focuses on the role of one of these, TRPM8, which has been implicated in cool sensation and cold pain by recent knockout mouse studies, but remarkably also appears capable of eliciting a novel analgesic gating control over noxious inputs in chronic pain states. We discuss hypothetical mechanisms that could bring about this composite profile. It is clear that new and highly selective agents will need to be developed to further evaluate the potential therapeutic opportunities offered by low temperature sensitive TRP channels.