Antinociceptive effect of 7-hydroxymitragynine in mice: Discovery of an orally active opioid analgesic from the Thai medicinal herb Mitragyna speciosa
Introduction
The leaf of Mitragyna speciosa (kratom in Thai) has been used in Thailand for its opium-like effect (Burkill, 1935) and its coca-like stimulant ability to combat fatigue and enhance tolerance to for hard work under a scoring sun Grewal, 1932, Suwanlert, 1975. Additionally, it has been used to treat diarrhea and to wean addicts off morphine Suwanlert, 1975, Jansen and Prast, 1988.
We have studied the pharmacological activities of an indole alkaloid isolated from Uncaria hook (Uncaria rhynchophylla) that is used clinically for hypertension Yano et al., 1991, Horie et al., 1992. Mitragynine (Fig. 1), the main component of the leaves of Mitragyna speciosa, is an indole alkaloid and structurally similar to Uncaria alkaloid. Mitragynine was reported to be comparable to codeine as an analgesic in dog, but it was not considered to act on opioid receptors Macko et al., 1972, Jansen and Prast, 1988. We studied the effect of mitragynine on guinea-pig ileum contraction and found that mitragynine is an opioid receptor agonist Watanabe et al., 1992, Watanabe et al., 1997. Some pharmacological investigations of mitragynine have also revealed that it has an antinociceptive action through the supraspinal opioid receptors, and that its action is dominantly mediated by μ- and δ-receptor subtypes in in vivo and in vitro studies Matsumoto et al., 1996a, Matsumoto et al., 1996b, Tohda et al., 1997, Thongpradichote et al., 1998.
Our previous study demonstrated a potent opioid agonistic property of mitragynine and its derivative compound mitragynine pseudoindoxyl in in vitro experiments (Yamamoto et al., 1999). In guinea-pig ileum, mitragynine and mitragynine pseudoindoxyl inhibit the vagally stimulated twitch contraction through opioid receptors. The effect of mitragynine pseudoindoxyl was 20-fold more potent than that of morphine. In mouse vas deferens, the effect of mitragynine pseudoindoxyl was 35-fold more potent than that of morphine. Mitragynine pseudoindoxyl was found to be a very potent μ- and δ-opioid agonist in both functional and binding assays (Yamamoto et al., 1999). In spite of its potent opioid effect, mitragynine pseudoindoxyl induced only a weak antinociceptive effect in the mouse tail-flick test in comparison with morphine (Takayama et al., 2002).
We previously compared the antinociceptive effect of Mitragyna speciosa and mitragynine in in vivo experiments, but the antinociceptive effect of mitragynine was less potent than that of the crude extract of Mitragyna speciosa Watanabe et al., 1992, Watanabe et al., 1999. This finding means that minor constituents of Mitragyna speciosa may have a very potent antinociceptive effect. We surveyed the other constituents of Mitragyna speciosa and found a new compound 7-hydroxymitragynine (Fig. 1), as a minor constituent of this plant (Ponglux et al., 1994). 7-Hydroxymitragynine exhibited a higher potency than mitragynine in the guinea-pig ileum test and a high affinity for μ-opioid receptors in binding assays (Takayama et al., 2002).
In the present study, we examined the opioid effect of 7-hydroxymitragynine on isolated guinea-pig ileum contraction and receptor binding assays. In addition, we investigated the antinociceptive activity of subcutaneous and oral administration of 7-hydroxymitragynine in tail-flick and hot-plate tests, comparing its activity with morphine.
Section snippets
Animals
Male albino Dunkin-Hartley guinea-pigs (320–570 g) purchased from Takasugi Lab. Animals Co., Ltd. (Saitama, Japan) and male ddY mice (22–38 g) from Japan SLC Inc. (Shizuoka, Japan) were used. Animals were housed under conditions with controlled temperature (24 ± 2°C) and a 12-h light/dark cycle (lighting on at 0700), for at least 1 week before the start experiment. Food and water were available ad libitum. The experiments were performed in compliance with “Guiding Principles for the Care and
Effect of 7-hydroxymitragynine on electrically induced contraction in guinea-pig ileum
The inhibitory effect of 7-hydroxymitragynine on twitch contraction induced by electrical stimulation in guinea-pig ileum is shown in Fig. 2. The addition of 7-hydroxymitragynine inhibited the electrically stimulated twitch contraction in a concentration-dependent manner as mitragynine and morphine did. The pD2 values were 7.78 ± 0.08 for 7-hydroxymitragynine, 6.50 ± 0.06 for mitragynine and 7.02 ± 0.08 for morphine. Consequently, 7-hydroxymitragynine exhibits about 13- and 46-fold higher
Discussion
We isolated a new compound, 7-hydroxymitragynine, as a minor constituent of the Thai medicinal herb Mitragyna speciosa (Ponglux et al., 1994). In the present study, we investigated its opioid effects in an isolated ileum contraction test, a receptor binding assay and antinociceptive tests, and found it to be a potent opioid agonist.
The electrically stimulated ileal preparation from guinea-pig was used as a model of the action of 7-hydroxymitragynine in its putative strong analgesic effects in
Conclusion
The Mitragyna alkaloid, 7-hydroxymitragynine induced dose-dependent antinociceptive effects in tail-flick and hot-plate tests in mice. This compound is structurally different from other opioid agonists, and has a more potent antinociceptive activity than morphine, especially with oral administration. 7-Hydroxymitragynine may be a seed for new analgesics due to its unique structure and a potent activity.
Acknowledgements
This work was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture, Japan.
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