The molecular and cellular basis of cold sensation

Of somatosensory modalities, cold is one of the more ambiguous percepts, evoking the pleasant sensation of cooling, the stinging bite of cold pain, and welcome relief from chronic pain. Moreover, unlike the precipitous thermal thresholds for heat activation of thermosensitive afferent neurons, thresholds for cold fibers are across a range of cool to cold temperatures that spans over 30 °C. Until recently, how cold produces this myriad of biological effects has been poorly studied, yet new advances in our understanding of cold mechanisms may portend a better understanding of sensory perception as well as provide novel therapeutic approaches. Chief among these was the identification of a number of ion channels that either serve as the initial detectors of cold as a stimulus in the peripheral nervous system, or are part of rather sophisticated differential expression patterns of channels that conduct electrical signals, thereby endowing select neurons with properties that are amenable to electrical signaling in the cold. This review highlights the current understanding of the channels involved in cold transduction as well as presents a hypothetical model to account for the broad range of cold thermal thresholds and distinct functions of cold fibers in perception, pain, and analgesia.