[Antinociceptive effects of counterirritants]

Counterirritants such as l-menthol, methyl salicylate, camphor, thymol and capsaicin are widely used in the treatment of mild pains and itches by topical application. However, little experimental research on counterirritants has been reported. In the present study, we investigated the antinociceptive effects and mechanisms of topically applied counterirritants, especially those of l-menthol. From the formalin test in mice, l-menthol (at a concentration of 1-30% in ethanol) showed a major effect in the early phase of pain response (0-5 min). In contrast, the antinociceptive effects of indomethacin (10 mg/kg, p.o.) were found only in the late phase of pain response (15-25 min). Furthermore, morphine (0.75-6 mg/kg, s.c.) dose-dependently inhibited both phases. l-Menthol-induced analgesia during the early phase was significantly blocked by naloxone and potentiated by bestatin. The antinociceptive effects of l-menthol were furthermore examined in dexamethasone-treated mice. l-Menthol also produced antinociceptive effects in the hot plate test of mice and hind paw pressure test of rats. l-Menthol showed mild surface and infiltrating anesthetic effects in guinea pigs. l-Menthol did not inhibit both carrageenin-induced paw edema of rats and the synthesis of prostaglandin E2 in vitro. Based on these findings, we proposed that l-menthol produces antinociceptive effects by activation of the endogenous opioid system and/or partially by local anesthetic actions without anti-inflammatory effects.