Two types of C nociceptors in human skin and their behavior in areas of capsaicin-induced secondary hyperalgesia

Peripheral nociceptor sensitization is accepted as an important mechanism of cutaneous primary hyperalgesia, but secondary hyperalgesia has been attributed to central mechanisms since evidence for sensitization of primary afferents has been lacking. In this study, microneurography was used to test for changes in sensitivity of C nociceptors in the area of secondary hyperalgesia caused by intradermal injection of capsaicin in humans. Multiple C units were recruited by electrical stimulation of the skin at 0.25 Hz and were identified as discrete series of dots in raster plots of spike latencies. Nociceptors slowed progressively during repetitive stimulation at 2 Hz for 3 min. According to their response to mechanical stimulation, nociceptors could be classified as either mechano-sensitive (CM) or mechano-insensitive (CM(i)). These two nociceptor subtypes had different axonal properties: CM(i) units slowed by 2% or more when stimulated at 0.25 Hz after a 3-min pause, whereas CM units slowed by < 1%. This stimulation protocol was used before capsaicin injection to identify nociceptor subtype without repeated probing, thus avoiding possible mechanical sensitization. Capsaicin, injected 10-50 mm away from the site of electrical stimulation, had no effect on any of 29 CM units, but induced bursts of activity in 11 of 15 CM(i) units, after delays ranging from 0.5 to 18 min. The capsaicin injections also sensitized a majority of the CM(i) units, so that 11 of 17 developed immediate or delayed responsiveness to mechanical stimuli. This sensitization may contribute a peripheral C fiber component to secondary hyperalgesia.