Molecular basis of peripheral innocuous cold sensitivity

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 biologic effects was unknown. However, recent advances in our understanding of cold mechanisms at the behavioral, physiologic, and cellular level have begun to provide insights into this sensory modality. The identification of a number of ion channels that either serve as the principal detectors of a cold stimulus in the peripheral nervous system, or are part of a differential expression pattern of channels that maintain cell excitability in the cold, endows select neurons with properties that are amenable to electric signaling in the cold. This chapter highlights the current understanding of the molecules involved in cold transduction in the mammalian peripheral nervous system, as well as presenting a hypothetic model to account for the broad range of cold thermal thresholds and distinct functions of cold fibers in perception, pain, and analgesia.