Mechanisms of Cold Pain

Avoidance of cold pain is an important survival mechanism. Intriguingly, whilst cooling can cause numbness, damage sensing mechanisms still seem to operate at low temperatures, and pain can be perceived from cooled damaged tissue. Recent studies have identified two cold-activated Transient Receptor Potential (TRP) channels present in sensory neurons as transducers of cold stimuli. TRPM8 seems to mediate responses to cooling whilst TRPA1 is activated, possibly indirectly, by more extreme cold conditions. The existence of cold-responsive neurons that do not express these channels suggest that other transducers of cold stimuli remain to be discovered. Subsequent action potential propagation from sensory neurons innervating cold tissues depends upon the presence of NaV1.8, the sole voltage-gated sodium channel that fails to inactivate at low temperatures. This may explain the remarkable specificity of NaV1.8 expression in nociceptive neurons, where it plays an important role in pain pathways.