Cutaneous injection of the capsaicin analog NE-21610 (Procter and Gamble) produces analgesia to heat but not mechanical stimuli in humans. The present study examined whether pretreatment of the skin with NE-21610 prevents the development of hyperalgesia following heat injury. On the 1st day testing, 7 volunteers received a 30-microl intradermal injection of vehicle to one volar forearm and 10 micrograms of NE-21610 to the other volar forearm. On the 2nd test day the subjects rated the intensity of pain to mechanical and heat stimuli before and after a burn (48 degrees C, 120 sec) to each injection site. At the vehicle site, the pain evoked by the burn was rated as moderate to strong. In addition, primary hyperalgesia to heat and mechanical stimuli, secondary hyperalgesia to mechanical stimuli, and flare were observed after the burn. In contrast, the pain evoked by the burn at the NE-21610-treated site was rated as weak, and primary hyperalgesia to heat and mechanical stimuli did not develop. In addition, the area of flare at the drug-tested site was smaller than that observed at the vehicle site, and no secondary hyperalgesia to mechanical stimuli was observed. These data suggest that pretreatment with the capsaicin analog NE-21610 may attenuate the pain and hyperalgesia associated with injury.