The nociceptive and anti-nociceptive effects of evodiamine from fruits of Evodia rutaecarpa in mice.

Recently, the authors reported that evodiamine, a major alkaloidal principle of Evodia fruits (Evodia rutaecarpa, Rutaceae), had vanilloid receptor agonistic activity comparable to capsaicin. In spite of the similarities in the actions of evodiamine and capsaicin in vitro, the effects of evodiamine on sensory neurons in vivo had not been investigated. We demonstrate here that evodiamine sensitizes and desensitizes the capsaicin-sensitive sensory afferents in mice, resulting in nociceptive action and antinociceptive actions. The nociceptive action (paw licking behaviour) was dose dependently induced by intradermal injection (i.d.) of evodiamine to the hind paw and was suppressed by the co-treatment with capsazepine, a vanilloid receptor specific agonist, in a dose-dependent manner. The treatment with higher dosages of evodiamine showed sustained antinociceptive effects. The acetic acid-induced writhing was significantly suppressed by the intraperitoneal evodiamine administration 3 days before, without any observable effects on spontaneous motor activity. The response of the isolated ileum from the mice with or without high dosages of evodiamine administration indicated the sensory neuron specific desensitizing effect of evodiamine. The isolated ileum from vehicle-treated mice contracted in response to both the sensory nerve stimulation by 10 microM capsaicin and the mimicked vagal stimulation by 2 microM carbachol. However, the isolated ileum from evodiamine-treated mice lost its response to sensory nerve stimuli but retained its response to vagus nerve stimuli. The suppression of acetic acid-induced writhing and the desensitization of visceral sensory neurons strongly correlated [regression coefficient (r) = 0.955]. Thus, we demonstrate that evodiamine shows the analgesic action by desensitizing sensory nerves.