The Nociceptive and Anti-Nociceptive Effects of Evodiamine from Fruits of Evodia rutaecarpa in Mice

Abstract

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 μM capsaicin and the mimicked vagal stimulation by 2 μM 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.

Key words

Evodiamine - capsaicin - capsazepine - vanilloid receptor - Evodia rutaecarpa - Rutaceae - nociception - desensitization

References

• 1 Matsuda H, Wu J X, Tanaka T, Iinuma M, Kubo M. Anti-nociceptive activities of 70 % methanol extract of Evodiae Fructus (Fruits of Evodia rutaecarpa var. bodinieri) and its alkaloidal components.  Biol Pharm Bull. 1997;  20 243-8
• 2 Kobayashi Y, Nakano Y, Hoshikuma K, Yokoo Y, Kamiya T. The bronchoconstrictive action of evodiamine, an indoloquinazoline alkaloid isolated from the fruits of Evodia rutaecarpa, on guinea-pig isolated bronchus: Possible involvement of vanilloid receptors.  Planta Medica. 2000;  66 526-30
• 3 Kobayashi Y, Hoshikuma K, Nakano Y, Yokoo Y, Kamiya  T. The positive inotropic and chronotropic effects of evodiamine and rutaecarpine, indoloquinazoline alkaloids isolated from the fruits of Evodia rutaecarpa, on the guinea pig isolated right atria: Possible involvement of vanilloid receptors.  Planta Medica. 2001;  67 244-8
• 4 Craft R M, Porreca F. Therapeutic potential of capsaicin-like molecules.  Life Science. 1992;  51 1767-75
• 5 Santos A RS, Calixto J B. Ruthenium red and capsazepine antinociceptive effect in formalin and capsaicin models of pain in mice.  Neuroscience Letters. 1997;  235 73-6
• 6 Holzer P. Capsaicin: Cellar targets, mechanisms of action, and selectivity for thin sensory neurons.  Pharmacological Reviews. 1991;  43 143-201
• 7 Rains C, Bryson H M. Topical capsaicin. A review of its pharmacological properties and therapeutic potential in post-herpetic neuralgia, diabetic neuropathy and osteoarthritis.  Drugs & Aging. 1995;  7 317-28
• 8 Lotti T, Teofoli P, Tsampau D. Treatment of aquagenic pruritus with topical capsaicin cream.  Journal of the American Academy of Dermatology. 1994;  30 232-5
• 9 Knight T E, Hayashi T. Solar (Brachioradial) pruritus - response to capsaicin cream.  International Journal of Dermatology. 1994;  33 206-9