Cold pain converts into burning pain - thermosensitivity of menthol activated C nociceptors

Introduction : Cold hyperalgesia is an important, but poorly understood symptom in neuropathic pain. A new model for cold pain showed that menthol acts to sensitize cold sensitive peripheral C nociceptors and activates cold specific A delta fibers by a cold channel (TRPM8). It is unclear at which environmental temperatures cold specific C nociceptors are activated by menthol. Methods : In 11 subjects menthol was topically applied to the forearm during local warming (39°C) and cooling (13°C). The skin was warmed and cooled, respectively, 5min prior to menthol and the skin temperature was kept constant during the 15min of menthol application. In a second approach menthol was applied on warm and cold skin during a selective A fiber block. Subjects rated temperature and pain sensations on NRS (temperature: -10 to +10, pain: 0 to 10). Investigations adhered to the Helsinki Declaration. Results : Warming of intact and A fiber-blocked skin induced a painless warm sensation prior to menthol and a warm sensation combined with significant burning pain during menthol. Cooling of intact skin induced a painless cold sensation prior to menthol which was reduced and accompanied by only moderate pain during menthol. During A fiber block menthol on cooled skin induced a significant pain without any temperature sensation. Conclusions : Cold specific C nociceptors are active in warm environment after menthol-sensitization and mediate ongoing pain. We suggest that the thermal range of the cold channel TRPM8 was extended after menthol-sensitization. Thus, pathologically sensitized cold nociceptors may cause spontaneous pain also in warm environments in patients with cold hyperalgesia. Menthol-induced pain was reduced in cooled skin due to central inhibition of C nociceptors exerted by concomitant activation of cold specific A fibers. Supported by the Alexander von Humboldt-Stifung, the DFG (Ba 1921/1–3), the BMBF (DNFS, 01EM01/04) and Pfizer Deutschland (unrestricted educational grant)