Human cutaneous C fibres activated by cooling, heating and menthol

Differential A-fibre block of human peripheral nerves changes the sensation evoked by innocuous cooling (∼24°C) of the skin from ‘cold’ to ‘hot’ or ‘burning’, and this has been attributed to activity in unidentified unmyelinated fibres that is normally masked or inhibited by activity in Aδ cold fibres. Application of the TRPM8 agonist menthol to the skin evokes ‘burning/stinging’ as well as ‘cold’, and the unpleasant sensations are also enhanced by A-fibre block. In this study we used microneurography to search for C fibres in human skin activated by cooling and menthol, which could be responsible for these phenomena. Afferent C fibres were classified by activity-dependent slowing as Type 1A (polymodal nociceptor), Type 1B (mechanically insensitive nociceptor) or Type 2 (cold sensitive), and their responses to heating and cooling ramps were measured before and after topical application of menthol preparations (2–50%). The only C fibres activated by menthol were the Type 2 fibres, which discharged vigorously with innocuous cooling and were strongly activated and sensitized to cooling by menthol. Unlike an Aδ cold fibre, they continued to discharge at skin temperatures down to 0°C, and most (13/15) were also activated by heating. We propose that the Type 2 C fibres, although resembling Aδ cold fibres in their responses to innocuous cooling and menthol, have a more complex sensory function, colouring with a ‘hot-burning’ quality the perceptions of low and high temperatures. Their bimodal thermoreceptive properties may help account for several puzzling psychophysical phenomena, such as ‘innocuous cold nociception’, ‘paradoxical heat’ and the thermal grill illusion, and also for some neuropathic pains.