Mechanisms Involved in the Antinociceptive Effects of 7-Hydroxycoumarin

Abstract

7-Hydroxycoumarin (umbelliferone, 1), the main metabolite of coumarin, has been reported to produce potent antinociceptive effects in animal models of pain. However, the biochemical events involved in antinociception mediated by 1 are currently not well understood. In the present study, the mechanisms by which 1 exerts its pharmacological actions were investigated. Acute pretreatment of mice with 1 produced a long-lasting antinociceptive effect against complete Freund’s adjuvant (CFA)-induced hyperalgesia. The subchronic administration of 1 inhibited CFA-induced hyperalgesia and paw edema, while it did not cause any apparent toxicity. Another set of experiments showed that 1 inhibited carrageenan-induced mechanical hyperalgesia, but not mechanical hyperalgesia induced by prostaglandin E2 (PGE2), suggesting that it acts upstream of PGE2. Treatment with 1 was able to prevent the plantar tissue neutrophil influx induced by local inflammatory stimuli. In addition, 1 exhibited inhibitory effects on the release of hyperalgesic cytokines (TNF-R and IL-1β) and the production of PGE2, a directly acting hyperalgesic mediator. The present results suggest that the antinociceptive effect of 1 is correlated with the inhibition of neutrophil migration, cytokine release, and PGE2 production and are supportive of the further investigation of the therapeutic potential of 1 to control inflammatory pain.