Converting cold into pain.

Cold temperature can evoke a wide spectrum of perceptual sensations that range from freshness to unpleasant cold or overt pain. In mammals, the detection of cold temperature is accomplished by the activation of different subsets of sensory terminals innervating the skin and mucosae. Direct recordings of corneal nerve endings, combined with studies of thermoreceptive neurons in culture, have allowed the characterization of ionic mechanisms involved in cold temperature sensing. In recent years, major progress has also taken place in the identification and operation of thermally gated ion channels, especially of the transient receptor potential (TRP) family. However, it is still uncertain how individual sensory endings can be activated with different thermal thresholds. In this review, we have considered the known properties of cold-sensitive receptors and their transduction mechanisms and related them to the sensations they evoke. We analyzed the evidence linking specific ion channels to the activation of particular sets of afferent fibers. In our view, cold thermotransduction is complex and involves the concerted operation of several ion channels. Excitatory effects of cationic channels (e.g., TRPs) balance their activity with several excitability brakes (e.g., potassium channels), leading to tunable levels of sensory thresholds and activity. Alteration in this fine balance may result in altered cold sensitivity, a frequent symptom in patients with peripheral nerve injury.