The dental phenolic medicaments, eugenol and guaiacol, are partly similar in chemical structure to capsaicin, the pungent constituent of chili peppers, which selectively activates sensory neurons via a specific receptor. We have previously demonstrated that these phenolic compounds show capsaicin-like action. In the present study, an attempt was made to investigate the possibility that these compounds interact with the same cellular site as capsaicin, by using capsazepine, a selective and competitive anta-gonist of capsaicin. Intrathecal (i.t.) treatment with eugenol (12.5 to 50 micrograms), guaiacol (25 to 150 micrograms), or capsaicin (1 to 4 micrograms) for 24 h dose-dependently inhibited the formalin-induced nociceptive response. Capsazepine (5, 10 micrograms, i.t.) shifted these dose-response curves in parallel to the right. Similarly, capsazepine abolished antinociceptive effects of eugenol (50 micrograms), guaiacol (150 micrograms), or capsaicin (2 micrograms) in the acetic acid writhing test. These results suggest that eugenol and guaiacol may exert their antinociceptive effects via the capsaicin receptor located on sensory terminals in the spinal cord.