Roles of capsaicin-insensitive nociceptors in cutaneous pain and secondaryhyperalgesia

Polymodal nociceptors respond to mechanical, thermal and chemical stimuli. Whereas sensitivities to heat and to the irritant substance capsaicin have recently been linked via the properties of the vanilloid receptor type 1 re ceptor ion channel, sensitivity to noxious mechanical stimuli such as the p inpricks used in clinical neurology seems to be unrelated. We investigated the peripheral neural basis of pinprick pain using quantitative psychophysi cal techniques combined with selective conduction block by nerve compressio n and selective desensitization by topical capsaicin treatment. Complete A- fibre block by compression of the superficial radial nerve (criterion: loss of first pain sensation) lowered the stimulus-response function for pinpri ck pain (-82 +/- 6% versus baseline). Topical pretreatment of the skin with a 10% capsaicin cream also lowered the pinprick stimulus-response function (-32 +/- 10%), whereas laser-evoked heat pain was eliminated completely (- 96 +/- 2%). Under combined capsaicin desensitization and A-fibre blockade, pinprick pain was eliminated completely (-98 +/- 1%). Intradermal injection of 40 mug capsaicin into normal skin between two skin areas that had been pretreated with either capsaicin cream or vehicle produced secondary hypera lgesia with a 260% enhancement of the stimulus-response function for pinpri ck pain in both areas. In contrast, axon reflexive flare spread only into t he vehicle-treated area. These results suggest that capsaicin-sensitive aff erents, including polymodal A-fibre and C-fibre nociceptors, make a small c ontribution to pinprick pain and that capsaicin-insensitive C-fibres do not contribute significantly to either mechanical or heat pain. Pinprick pain is mediated primarily by capsaicin-insensitive A-fibre nociceptors, which i nclude high-threshold mechanoreceptors and type I mechano-heat nociceptors. In addition, central sensitization to input from these A-fibre nociceptors is the primary mechanism that accounts for the enhanced pain in response t o punctate mechanical stimuli in the zone of secondary hyperalgesia. These capsaicin-insensitive A-fibre nociceptors may also mediate hyperalgesia in neuropathic pain.