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

doi:10.1016/S0306-3623(98)00265-1

General Pharmacology: The Vascular System

Volume 33, Issue 1, July 1999, Pages 73-81

General Pharmacology...

https://doi.org/10.1016/S0306-3623(98)00265-1 Get rights and content

Abstract

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 μ-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 μ-receptor antagonist naloxonazine. It was also antagonized by the δ-receptor antagonist naltrindole in the vas deferens. Mitragynine pseudoindoxyl showed a similar binding affinity to DAMGO and naltrindole at μ- and δ-receptors, respectively. However, the affinity at κ-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 μ-receptors and in mouse vas deferens through δ-receptors.

Section snippets

Materials and methods

Male, albino Dunkin-Hartley guinea pigs (300–400 g) purchased from Takasugi Lab. Animals Co. Ltd. (Saitama, Japan) and male ddY mice (30–37 g) from Japan SLC Inc. (Shizuoka, Japan) were used. The segments of guinea pig ileum were removed in Krebs-Henseleit solution (Cox and Weinstock, 1966). A whole brain (excluding cerebellum) was quickly removed and placed in ice-cold 50 mM Tris HCl buffer, pH 7.4 at 25°C, weighed, and immediately frozen in dry ice containing acetone. Frozen brains were

Effect of mitragynine pseudoindoxyl on electrical stimulation-induced contraction

The inhibitory effect of mitragynine pseudoindoxyl on contraction evoked by single pulse electrical stimulation in the guinea pig ileum is shown in Fig. 2. The mean amplitude of electrical contraction was about 20% of the maximal response to acetylcholine (3 μM). The solvent (dimethyl sulfoxide 0.1%) used in the experiment did not affect the contraction (0.3 ± 1.6% inhibition, n = 3).

Mitragynine pseudoindoxyl inhibited the electrically stimulated ileum contraction in a concentration-dependent

Discussion

The electrically stimulated ileal preparation from guinea pig and vas deferens from mouse, and receptor binding assay with guinea pig brain homogenates were used to study the mode of action of mitragynine pseudoindoxyl in their putative strong analgesic effects in mice.

At first, we studied the effect of mitragynine pseudoindoxyl on electrical stimulation-induced contraction in guinea pig ileum. The contraction was abolished by tetrodotoxin and atropine, but not by hexamethonium. Therefore, the

Summary

Mitragynine pseudoindoxyl is a compound related to mitragynine, which is structurally unrelated to morphine and has opiate-like antinociceptive activity (Zarembo et al., 1974). Mitragynine is a main alkaloid isolated from leaves of M. speciosa, a Thai folk medicine with opiate-like medicinal use. Effects of mitragynine pseudoindoxyl on electrically stimulated contraction in guinea pig ileum and mouse vas deferens, and its binding affinity in the guinea pig brain membranes were studied in order

Acknowledgements

This study was supported in part by a grant for the Mombusho International Scientific Research Program: Joint Research (No. 06044035) and by Grants-in-Aid for Scientific Research (No. 08557128, 10557229), and for Encouragement of Young Scientists (No. 09771965) from the Ministry of Education, Science, Sports and Culture, Japan. S. Horie is the recipient of a grant from Kato Memorial Bioscience Foundation, Japan.

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

Abstract

Section snippets

Materials and methods

Effect of mitragynine pseudoindoxyl on electrical stimulation-induced contraction

Discussion

Summary

Acknowledgements

Eur J Pharmacol

Neurosc Lett

Trends Pharmacol Sci

Life Sci

J Ethnopharmacol

Eur J Pharmacol

Trends Neurosci

Life Sci

Eur J Pharmacol

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Eur J Pharmacol

Life Sci

Neurochem Int

Life Sci

Some quantitative uses of drug antagonists

Br J Pharmacol

Demonstration of a specific dynorphin receptor in guinea pig ileum myenteric plexus

Nature

Use of the mouse vas deferens to determine μ, δ, and κ receptor affinities of opioid antagonists

Receptor

The effect of analgesic drugs on the release of acetylcholine from electrically stimulated guinea-pig ileum

Br J Pharmacol Chemother

International union of pharmacology. XII. Classification of opioid receptor

Pharmacol Rev

Evidence for lack of modulation of μ-opioid agonist action by δ-opioid agonists in the mouse vas deferens and guinea-pig ileum

Br J Pharmacol

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