Opioid receptor agonistic characteristics of mitragynine pseudoindoxyl in comparison with mitragynine derived from Thai medicinal plant Mitragyna speciosa.

We have previously elucidated the opiate-like action of mitragynine, an active principle isolated from the Thai medicinal plant Mitragyna speciosa. In the present study, effects of the related compound, mitragynine pseudoindoxyl on electrically stimulated contraction in guinea pig ileum and mouse vas deferens, and on its binding affinity in the guinea pig brain membranes were studied. Mitragynine pseudoindoxyl inhibited the electrically stimulated ileum and mouse vas deferens contractions in a concentration-dependent manner. In the ileum, the effective concentration is in an nM order, being nearly equivalent to reported concentrations of the micro-opioid receptor agonist [D-Ala2, Met-Phe4, Gly-ol5] enkephalin (DAMGO), and is 100- and 20-fold smaller than those of mitragynine and morphine, respectively. In the vas deferens, it is 35-fold smaller than that of morphine. The inhibitory action of mitragynine pseudoindoxyl in the ileum was antagonized by the non-selective opioid receptor antagonist naloxone and the micro-receptor antagonist naloxonazine. It was also antagonized by the delta-receptor antagonist naltrindole in the vas deferens. Mitragynine pseudoindoxyl showed a similar binding affinity to DAMGO and naltrindole at micro- and delta-receptors, respectively. However, the affinity at kappa-receptors was negligible. The present study demonstrates that mitragynine pseudoindoxyl, a novel alkaloid structurally different from other opioid agonists, acts on opioid receptors, leading to a potent inhibition of electrically stimulated contraction in the ileum through the micro-receptors and in mouse vas deferens through delta-receptors.

Inhibitory effect of mitragynine, an alkaloid with analgesic effect from Thai medicinal plant Mitragyna speciosa, on electrically stimulated contraction of isolated guinea-pig ileum through the opioid receptor.

Effect of mitragynine, an indole alkaloid isolated from Thai medicinal plant kratom (Mitragyna speciosa), on electrically stimulated contraction was studied in the guinea-pig ileum. Mitragynine (1 nM-3 microM) inhibited the ileum contraction elicited by electrical stimulation, and its pD2 value was 6.91 +/- 0.04 (n = 5). Morphine (1 nM-1 microM) also inhibited the electrically stimulated contraction in a concentration-dependent manner (pD2 7.68 +/- 0.11; n = 5). Mitragynine was 10 fold less potent than morphine. Mitragynine (3-10 microM) did not show any effect on the smooth muscle contraction induced by acetylcholine or histamine. Naloxone (10-300 nM) reversed the inhibitory effect of mitragynine on electrically stimulated contraction. Furthermore, naloxone showed a shift of concentration-response curve of mitragynine to the right. There was no significant difference in the affinity of naloxone (i.e. pA2) in the presence of mitragynine or morphine. Mitragynine (3-10 microM) inhibited the naloxone-precipitated withdrawal contraction following a brief (5 min) exposure of the ileum to morphine. Tetrodotoxin (1 microM) and atropine (1 microM) inhibited the withdrawal contraction. The present results suggest that mitragynine inhibits the electrically stimulated contraction of guinea-pig ileum through the opioid receptor.