Encoding of burning pain from capsaicin-treated human skin in two categories of unmyelinated nerve fibres

Burning pain was induced in healthy human subjects by intracutaneous injections of capsaicin (20 μl, 0.1%) in the innervation territory of the cutaneous branch of the peroneal nerve and the pain responses were compared with the activation patterns of afferent C-fibres recorded by microneurography. Responsiveness of single units to mechanical or heat stimuli or to sympathetic reflex provocation tests was determined by transient slowing of conduction velocity following activation (marking technique). Capsaicin activated each of 12 mechano-responsive and 17 of 20 mechano-insensitive C-units. However, the duration of the responses to capsaicin was significantly longer in mechano-insensitive C-units (median 170 s; quartiles 80–390) compared with mechano-responsive C-units (8 s; 4–10). The activation times of mechano-insensitive C-units closely matched the duration of capsaicin-induced pain responses, whereas activation of mechano-responsive C-units was too short to account for the duration of the burning pain. The latter generally were desensitized to mechanical stimulation at the injection site, whereas 8 of 17 of the originally mechano-insensitive C-units became responsive to mechanical probing at the injection site after capsaicin. Responses typically started several seconds after the onset of the mechanical stimulus in parallel with pain sensations. We did not observe sensitization to brushing or to punctate stimuli in uninjured parts of the innervation territory. Differential capsaicin sensitivity adds to the cumulating evidence for the existence of two categories of functionally different nociceptors in human skin, with a special role for mechano-insensitive fibres in sensitization and hyperalgesia. Possible structural differences between these two categories are discussed, including the role of tetrodotoxin-resistant sodium channels.