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Inhibitory effect of mitragynine, an analgesic alkaloid from Thai herbal medicine, on neurogenic contraction of the vas deferens

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Abstract

The effect of an indole-alkaloid mitragynine isolated from the Thai medicinal herb kratom (Mitragyna speciosa) on neurogenic contraction of smooth muscle was studied in guinea-pig vas deferens. Mitragynine inhibited the contraction of the vas deferens produced by electrical transmural stimulation. On the other hand, mitragynine failed to affect the responses to norepinephrine and ATP. Mitragynine did not reduce KCl-induced contraction in the presence of tetrodotoxin, prazosin and alpha,beta-methylene ATP. Mitragynine inhibited nicotine- or tyramine-induced contraction. By using the patch-clamp technique, mitragynine was found to block T- and L-type Ca2+ channel currents in N1E-115 neuroblastoma cells. In the Ca2+ measurement by a fluorescent dye method, mitragynine reduced KCl-induced Ca2+ influx in neuroblastoma cells. The present results suggest that mitragynine inhibits the vas deferens contraction elicited by nerve stimulation, probably through its blockade of neuronal Ca2+ channels.

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... For this reason, MG is assumed to be the major chemical responsible for the effects of the plant. Thus, there has been an increased interest in characterising the chemical, toxicological and pharmacological properties of MG in recent years (Matsumoto et al. 1996a;Matsumoto et al. 2005b;Reanmongkol et al. 2007;Takayama 2004;Takayama et al. 2002;Jansen and Prast 1988;Azizi et al. 2010;Janchawee et al. 2007;Macko et al. 1972;Shellard 1974). Many scientific reports have indicated that MG produces a variety of pharmacologic effects, both in vivo and in vitro. ...
... The findings show that MG can elicit analgesic effects by acting on opioid systems (Matsumoto et al. 1996a;Stolt et al. 2014). Other physiological effects include the inhibition of ileum motility (Watanabe et al. 1997) and vas deferens contractions of smooth muscle (Matsumoto et al. 2005b), as well as the inhibition of gastric acid secretion (Tsuchiya et al. 2002), which is consistent with the actions of morphine. In addition, studies with opioid receptor antagonists indicate that the effects are primarily mediated by the actions on opioid receptors (Matsumoto et al. 2005b;Watanabe et al. 1997). ...
... Other physiological effects include the inhibition of ileum motility (Watanabe et al. 1997) and vas deferens contractions of smooth muscle (Matsumoto et al. 2005b), as well as the inhibition of gastric acid secretion (Tsuchiya et al. 2002), which is consistent with the actions of morphine. In addition, studies with opioid receptor antagonists indicate that the effects are primarily mediated by the actions on opioid receptors (Matsumoto et al. 2005b;Watanabe et al. 1997). ...
Article
Mitragynine (MG) is the primary active alkaloid extracted from the leaves of Mitragyna speciosa or kratom and exhibits pharmacological activities mediated by opioid receptors. The plant has been traditionally used for its opium and psychostimulant-like effects to increase work efficiency or as a substitute in the self-treatment of opiate addiction. The present study was performed to investigate the discriminative stimulus effects of MG in rats. The pharmacological mechanism of MG action and its derivative, 7-hydroxymitragynine (7-HMG) with a specific focus on opioid receptor involvement was examined in rats trained to discriminate morphine from vehicle. In order to study the dual actions of MG, the effect of cocaine substitution to the MG discriminative stimulus was also performed in MG-trained rats. Male Sprague Dawley rats were trained to discriminate MG from vehicle in a two-lever drug discrimination procedure under a tandem variable-interval (VI 60') fixed-ratio (FR 10) schedule of food reinforcement. Rats acquired the MG discrimination (15.0 mg/kg, i.p.) which was similar to the acquisition of morphine discrimination (5.0 mg/kg, i.p.) in another group of rats. MG substituted fully to the morphine discriminative stimulus in a dose-dependent manner, suggesting pharmacological similarities between the two drugs. The administration of 7-HMG derivative in 3.0 mg/kg (i.p.) dose engendered full generalisation to the morphine discriminative stimulus. In addition, the MG stimulus also partially generalised to cocaine (10.0 mg/kg, i.p.) stimulus. The present study demonstrates that the discriminative stimulus effect of MG possesses both opioid- and psychostimulant-like subjective effects.
... Although it is well-established that mitragynine and 7-hydroxymitragynine bind to opioid receptors, the exact nature of the interaction remains unclear (Eastlack et al., 2020). Early work by Takayama and Matsumoto suggested that mitragynine mediated its effects via mu opioid and delta opioid receptor agonism, while 7-hydroxymitragynine was more selective for mu receptors and kappa receptors Matsumoto et al., 2005). 7-Hydroxymitragnine was reported to be 13-fold and 46-fold more potent than morphine and mitragynine, respectively. ...
... 7-Hydroxymitragnine was reported to be 13-fold and 46-fold more potent than morphine and mitragynine, respectively. In-vivo studies have shown that 7-hydroxymitragynine exhibits cross-tolerance to morphine and precipitated withdrawal following naloxone administration (Matsumoto et al., 2005). More recent studies suggest that both compounds are mixed opioid receptor agonists/antagonists, with partial mu-receptor agonism and competitive antagonism at kappa and delta receptors (Kruegel et al., 2016). ...
... Additional reports suggest that mitragynine can reduce neuropathic pain through α-adrenoceptor activity, further emphasizing the need to fully explore the influence of kratom alkaloids on the nervous system (Foss et al., 2020). Additional non-opioid mediated pathways involve the blockade of calcium channels (Matsumoto et al., 2005) and inhibition of COX-2 and prostaglandin E 2 mRNA expression (Eastlack et al., 2020;Shaik Mossadeq et al., 2009; Utar, Majid, Adenan, Jamil, & Lan, 2011). ...
Article
Kratom is a botanical substance derived from the leaves of Mitragyna speciosa. Although kratom has been used traditionally in Southeast Asia for over a century, recreational use and non‐medically supervised use of the drug in the West has escalated considerably over the past decade. Viewed as a legal, “safe” or “natural” alternative to opioids, kratom has gained widespread use for the non‐medically supervised treatment of chronic pain, anxiety, and opioid withdrawal. Kratom consists of a complex mixture of more than 50 alkaloids, of which mitragynine and 7‐hydroxymitragynine are the principal compounds of interest due to their abundance and heightened affinity for the mu opioid receptor, respectively. Mitragynine, which is structurally and pharmacologically distinct from traditional opioids, exhibits a multimodal mechanism of action which accounts for its complex adrenergic, serotonergic, and opioid‐like effects. Adverse effects including fatalities have been associated with kratom's use, often in combination with other drugs. While users report numerous benefits associated with its use, lack of regulatory control and escalating use among individuals with opioid use disorder has attracted widespread concern. In this review the origins, pharmacology, uses, effects, and analysis of the drug are reviewed from a toxicological standpoint. This article is categorized under: • Toxicology > New Psychoactive Substances • Toxicology > Opioids • Toxicology > Plants and Poisons Abstract Kratom: A systematic review of toxicological issues.
... 6,[9][10][11]14 In the West, kratom is increasingly being used by individuals for the self-management of pain or withdrawal from opioid drugs such as heroin and prescription pain relievers. 20 35 In addition, a variety of chemical compounds have been isolated from kratom and shown to exhibit opioid-like activity on smooth muscle systems 31,33,34 and in ligand-binding studies. 39,40 Most notably, many of the central nervous system and peripheral effects of these kratom-derived substances are sensitive to inhibition by opioid antagonists. ...
... 39,40 Most notably, many of the central nervous system and peripheral effects of these kratom-derived substances are sensitive to inhibition by opioid antagonists. [31][32][33][34][39][40][41] 44 13-and 46-fold higher potency than morphine and mitragynine, respectively Potency and quick-acting characteristics may be caused by introduction of -OH group on C7 position Induces clinically significant antinociceptive responses in a dose-dependent manner Speciociliatine 30,44 C3 stereoisomer of mitragynine Inhibits twitch contraction in naloxoneinsensitive manner May inhibit acetylcholine release from presynaptic nerve through means other than opioid receptor stimulation Paynantheine 40,44 Inhibits twitch contraction in naloxoneinsensitive manner Inhibits muscarine receptors on ileal smooth muscle Speciogynine 40,44 Inhibits twitch contraction in naloxoneinsensitive manner Inhibits muscarine receptors in ileal smooth muscle ...
... 30,32,40 These agents also produce opioid-like effects on organs such as the intestines and male internal genitalia. 33,34 Moreover, when they are given to animals for 5 days or longer, both compounds produce a state of physical dependence, with withdrawal symptoms that resemble those of opioid withdrawal. 31,32,41 In addition, ligand-binding studies and those using opioid antagonists indicate that these effects are largely mediated by means of actions on μand δ-type opioid receptors. ...
Article
Full-text available
Kratom (Mitragyna speciosa) is a plant indigenous to Thailand and Southeast Asia. Kratom leaves produce complex stimulant and opioid-like analgesic effects. In Asia, kratom has been used to stave off fatigue and to manage pain, diarrhea, cough, and opioid withdrawal. Recently, kratom has become widely available in the United States and Europe by means of smoke shops and the Internet. Analyses of the medical literature and select Internet sites indicate that individuals in the United States are increasingly using kratom for the self-management of pain and opioid withdrawal. Kratom contains pharmacologically active constituents, most notably mitragynine and 7-hydroxymitragynine. Kratom is illegal in many countries. Although it is still legal in the United States, the US Drug Enforcement Administration has placed kratom on its "Drugs and Chemicals of Concern" list. Physicians should be aware of the availability, user habits, and health effects of kratom. Further research on the therapeutic uses, toxic effects, and abuse potential of kratom and its constituent compounds are needed.
... At cellular level, mitragynine blocked neuronal Ca 2+ channels, which partly contributes to the inhibition of neurotransmitter release from the nerve endings at the vas deferens. The neuronal Ca 2+ channel-blocking effect of mitragynine is believed to be a general mechanism for other physiological effects (Matsumoto et al., 2005b). Mitragynine was also found to inhibit forskolinstimulated cAMP formation in vitro which can be blocked by the opioid receptor antagonist, naloxone (Tohda et al., 1997;Jamil et al., 2013). ...
... Many scientific reports provide accumulating evidences that active compounds present in M. speciosa produce a variety of pharmacologic effects, both in vivo and in vitro. One of the pharmacologic effects include the inhibition of ileum and vas deferens contraction (Matsumoto et al., 2005b) as well as the inhibition of gastric acid secretion (Tsuchiya et al., 2002) which is comparable to the actions of morphine. ...
... In our lab, research on some basic aspects of these pathways has been undertaken to study the neurobiology of mitragynine reward. Since pharmacological studies revealed that mitragynine has agonistic effects on opioid receptors Matsumoto et al., 2005b;Taufik Hidayat et al., 2010), there is a possibility that mitragynine may shares the common reward circuit as above. ...
... In particular, extracts obtained from Psychotria laciniata containing Z-vallesiachotamine (29), and Evallesiachotamine (30) (Fig. 7) as major compounds, showed high potency against monoamine oxidase A (MAO-A) and only moderate potency against monoamine oxidase B (MAO-B) [27]. Moreover, Z-vallesiachotamine (29), E-vallesiachotamine (30), and vallesiachotamine lactone (31) (Fig. 7) were shown to inhibit butyrylcholinesterase (BChE) and MAO-A with IC 50 values ranging from 7.08 to 14 M for BChE inhibition and from 0.85 to 2.14 M for MAO-A inhibition [28]. Finally, using a computational structurebased approach, it was investigated if these three alkaloids bind sirtuin 1 and sirtuin 2. The compounds demonstrated a SIRT1 inhibitory profile comparable to that of sirtinol (nonspecific SIRT inhibitor). ...
... The results demonstrated that mitragynine (32) inhibited the contraction of guinea-pig vas deferens produced by electrical transmural stimulation. More precisely, mitragynine (32) was found to block T-and L-type Ca 2+ channel currents and reduced KClinduced Ca 2+ influx in N1E-115 neuroblastoma cells [30]. ...
... Mitragyna speciosa -analgesic activity [30,35,37] Mitragyna speciosa -moderate opioid agonist activity [32,33] -partial agonist of opioid receptors, high affinity and selectivity for -opioid receptors [34][35] -high affinity for μ-and -opioid receptors [36] ( ...
Article
Corynantheine alkaloids with a tetracyclic indole[2,3-a]-quinolizidine motif are an important issue in academia and in the life science industries due to their broad bioactivity profile. In particular, the main biological effects described for indoloquinolizidines include analgesic, anti-inflammatory, antihypertensive, and antiarrhythmic activities, as well as inhibition of multiple ion channels, affinity for opioid receptors, and activity against Leishmania. For that reason, in the last decades, numerous efforts have been invested in the development of novel synthetic strategies to obtain the indole[2,3-a]-quinolizidine system. This review focuses on the synthetic methodologies developed to target the most important alkaloids of this family, and highlights the potential use of these alkaloids or analogs to treat several diseases, ranging from cancer to neurodegenerative disorders.
... At cellular level, mitragynine inhibits neurotransmitter release from the nerve endings at the vas deferens, partly through the blockade of neuronal Ca 2+ channels (Matsumoto et al., 2005b). The authors proposed the neuronal Ca 2+ channel-blocking effect of mitragynine as a general mechanism for the analgesic and other physiological actions of mitragynine. ...
... Opioid agonist activity is measured as the inhibition of the twitch contraction, which is reversed by the opioid receptor antagonist naloxone. M. speciosa preparations, mitragynine, and other isolated M. speciosa indole alkaloids as well as mitragynine derivatives inhibited the electrically stimulated contraction Horie et al., 2005;Matsumoto et al., 2005b). ...
Article
Full-text available
Kratom (or Ketum) is a psychoactive plant preparation used in Southeast Asia. It is derived from the plant Mitragyna speciosa Korth. Kratom as well as its main alkaloid, mitragynine, currently spreads around the world. Thus, addiction potential and adverse health consequences are becoming an important issue for health authorities. Here we reviewed the available evidence and identified future research needs. It was found that mitragynine and M. speciosa preparations are systematically consumed with rather well defined instrumentalization goals, e.g. to enhance tolerance for hard work or as a substitute in the self-treatment of opiate addiction. There is also evidence from experimental animal models supporting analgesic, muscle relaxant, anti-inflammatory as well as strong anorectic effects. In humans, regular consumption may escalate, lead to tolerance and may yield aversive withdrawal effects. Mitragynine and its derivatives actions in the central nervous system involve μ-opioid receptors, neuronal Ca2+ channels and descending monoaminergic projections. Altogether, available data currently suggest both, a therapeutic as well as an abuse potential.
... However, these indole alkaloids are structurally and pharmacologically distinct from other opioids, hence producing partially overlapping but different effects [8]. Additionally, mitragynine appears to have an additional analgesic effect via the activation of alpha-2 adrenergic receptors, inhibition of COX-2, and calcium channel blockade [9,10]. Mitragynine also has some affinity to other receptors, such as serotonin, dopamine, and adenosine receptors. ...
Article
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Ketum use is significantly prevalent amongst individuals in the northern states of Peninsular Malaysia. This study aims to investigate the prevalence and psychosocial correlates of Ketum use in individuals who are in the Methadone Maintenance Therapy (MMT) Programme at the Hospital Taiping. This is a cross-sectional study conducted in the methadone clinic at the Hospital Taiping. The study instruments used were Subjective Opiate Withdrawal Scale (SOWS), Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) questionnaire, and Kratom Dependence Scale (KDS). A total of 215 subjects were recruited for this study. The prevalence of ketum users was 49.3% (n = 106). Chinese and Indian ethnicity had a lower tendency to use ketum compared to Malay ethnicity, with OR = 0.386 (95% CI 0.134, 1.113) and 0.119 (95% CI 0.035, 0.408), respectively. Individuals who used other illicit drugs had a higher tendency to use ketum with the adjusted OR = 9.914 (95% CI: 1.109, 88.602). Every one unit increase in SOWS increased the odds of being a ketum user by 1.340 (95% CI: 1.070, 1.677), whereas every one unit increase in duration in the MMT programme reduced the odds of being a ketum user by 0.990 (95% CI: 0.982, 0.998). Ketum use is prevalent amongst those in the MMT programme in this study. The high prevalence of ketum use is of concern and further interventions should be carried out to address this.
... The central monoaminergic system was shown to be involved in the pain modulation activity of mitragynine. The noxious stimulus test showed the descending noradrenergic and serotonergic systems modulates the anti-nociceptive activity of mitragynine on tail flick test (mechanical stimulation) while the descending noradrenergic system regulates the anti-nociceptive activity of mitragynine hot-plate test (thermal stimulation) [19] . The mitragynine suppression of head twitch response caused by 5-methoxy-N,N-dimethyltryptamine demonstrated the effect of mitragynine on serotonergic function in the brain [20] . ...
Article
Full-text available
Drug abuse is a major concern worldwide and has remained so for decades. Beside synthetic drugs, the misuse of psychoactive compounds from natural products as drugs of abuse contributes to this incessant concern. Reports on misuse of mitragynine, an alkaloid from the plant Mitragyna speciosa Korth (Kratom or Ketum) as a substituent for opioid withdrawal syndrome are becoming prevalent in recent years, and extended beyond the geographical boundaries of the plant. Although there are comprehensive data available on chemical and pharmacological properties of mitragynine particularly on its opioid-like analgesic property, the mechanism of actions for its abuse liabilities remain unclear. This article presents the plausible leads for mitragynine abuse liability by reviewing the established roles of endocannabinoid system as a molecular target where the opioids and cannabinoids act. These leads build for the arguments to posit the involvement of ubiquitous endocannabinoid receptors within the cerebellum and the evidences for cerebellar non-motor functions (brain reward processes, drug-induced long term memory and plasticity, and structural alterations linked to addiction) towards a potential new player as the basis for abuse liability of Kratom, accumulating to addiction.
... The connection between synapses is impaired due to the blockage of the receptors and will thus prevent LTP from being induced (18). Several alkaloids, such as mitragynine (19,20), rhynchophylline(1), and corynoxine A (21), have been reported to act as calcium channel blockers. In our study, we speculate that the actions of these alkaloids contributed to the blockage of LTP at the Schaffer collateral pathway of the CA1 region the hippocampus. ...
Article
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Background: Mitragyna speciosa (MS) or ketum is primarily found in Southeast Asia, particularly in northern Malaysia and Thailand. The medicinal value of this plant has attracted significant attention from both herbal medicine practitioners and scientists worldwide. Despite having illegal consumption status, the plant merits study. We conducted a series of experiments to test our hypothesis that ketum impairs both learning and memory in rats. Methods: Ketum leaves were extracted using methanol and standardised for the amount of its pure compound, mitragynine. Rats were divided into groups for a passive avoidance task and long-term potentiation (LTP) extracellular recording. In the extracellular recording condition, rats were grouped into control, MS100 (100 mg/kg of ketum extract), MS200 (200 mg/kg of ketum extract), and MS500 (500 mg/kg of ketum extract) groups. An additional group that received morphine was included in the passive avoidance task (10 mg/kg), and there were six animals per group. Rats received daily treatments orally for 28 days for both experiments. Result: Using a passive avoidance task, our data revealed that the rats' memory significantly increased with increasing doses of MS compared to the morphine-treated group. Our findings from LTP recordings showed that LTP was fully blocked by the higher doses of MS. Conclusion: We speculate on the possibility that additional factors were involved in the passive avoidance task because it was an in vivo animal study, while the LTP experiment solely involved brain slices.
... Available evidence suggests that kratom has potential for addiction (Hassan et al. 2013). Studies in mice indicate that some of the kratom metabolites and derivatives are rewarding and result in tolerance, as assessed by a significant reduction in analgesia (Matsumoto et al. 2005(Matsumoto et al. , 2008. Signs of physical withdrawal were noted in mice after injection with the opioid inhibitor naloxone. ...
Article
Full-text available
Kratom (Mitragyna speciosa) is a psychoactive plant that has been used since at least 1836 in folk medicine in Southeast Asian countries. More recently, kratom has become widely available in the West and is used for both recreational and medicinal purposes. There has, however, been little scientific research into the short- and long-term effects of kratom in humans, and much of the information available is anecdotal. To supplement the increasing scientific understanding of kratom's pharmacology and research into its effects in animals, we report the results of a qualitative analysis of first-hand descriptions of human kratom use that were submitted to, and published by, a psychoactive substance information website (Erowid.org). Themes that emerged from these experience reports indicate that kratom may be useful for analgesia, mood elevation, anxiety reduction, and may aid opioid withdrawal management. Negative response themes also emerged, indicating potential problems and unfavorable "side" effects, especially stomach upset and vomiting. Based on our analyses, we present preliminary hypotheses for future examination in controlled, quantitative studies of kratom.
... 10 In addition, animal studies suggest that MG has agonist activity at α 2 -adrenergic receptors, perhaps contributing to its effect in mitigating opioid withdrawal symptoms. 15,16 However, the analgesic effect of MG is less potent than that of the crude extract of Mitragyna speciosa. The opium-like effect of this plant cannot be fully explained by that of MG. ...
Article
In the presented studies, the herbal drug Kratom (Mitragyna speciosa) was investigated regarding its metabolism and its toxicological analysis in rat and human urine. Depending on the plant species and plant parts the three most abundant alkaloids of Mitragyna speciosa are MG, PAY and the MG diastereomer SG. Further alkaloids are the MG diastereomers SC and MC and ISO-PAY the diastereomer of PAY. The diastereomers of MG and PAY were mainly metabolized by hydrolysis of the methylester in position 16 and O-demethylation of the 9-methyoxy group. Further steps were the O-demethylation of the 17-methoxy group, followed, via the corresponding aldehydes, by oxidation to carboxylic acids or reduction to the correspondent alcohols, and combinations of these steps. As metabolic phase II reactions, partial glucuronidation and sulfation were observed. The metabolism study showed that all diastereomers of MG and PAY were extensively metabolized in rats and humans with some differences, particularly in phase II metabolism. In the case of Kratom, the target analytes for the toxicological analysis were the derivatized MG parent substance, the 9-O-demethyl metabolite of MG, the free carboxy group metabolite of MG, and the 9-O-demethyl-16-carboxy metabolite of MG.
... Comparable to the findings of our study, Calixto et al. (1984) described how the alkaloids from Phyllanthus sellowianus extract, exhibited antispasmodic activity in rat uterus as well as in aortic ring and ileum smooth muscle. Additionally, the other alkaloids, for example, mitragynines, have also been reported to reduce KCl-induced Ca influx in neuroblastoma cells (Matsumoto et al. 2005). Several effects of flavonoids on smooth muscle contraction have already been clearly described. ...
Article
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Ginseng Java or Talinum paniculatum (Jacq.) Geartn has long been used in herbal recipes because of its various therapeutic properties. Ginseng Java is believed to be beneficial to the female reproductive system by inducing lactation and restoring uterine functions after the postpartum period. There are, however, no scientific data on verifying the effects on the uterus to support its therapeutic relevance. Therefore, the purpose of this study was to investigate the effects of Ginseng Java root extract and its possible mechanism(s) of action on uterine contractility. Female virgin rats were humanely killed by CO2 asphyxia and uteri removed. Isometric force was measured in strips of longitudinal myometrium. The effects of Ginseng Java root extract at its IC50 concentration (0.23 mg/mL) on spontaneous, oxytocin-induced (10 nmol/L), and depolarized (KCl 40 mmol/L) contraction were investigated. After establishing regular phasic contractions, the application of Java root extract significantly inhibited spontaneous uterine contractility (n = 5). The extract also significantly inhibited the contraction induced by high KCl solution (n = 5) and oxytocin (n = 5). The extract also inhibited oxytocin-induced contraction in the absence of external Ca entry (n = 7) and the tonic force induced by oxytocin in the presence of high KCl solution. Taken together, the data demonstrate a potent and consistent ability of extract from Ginseng Java root to reduce myometrial contractility. The tocolytic effects were demonstrated on both spontaneous and agonist-induced contractions. The fact that force was inhibited in depolarized conditions suggests that the possible mechanisms may be blockade of Ca influx via L-type Ca channels. The data in Ca-free solutions suggest that the extract also reduces IP3-induced Ca release from the internal store. These tocolytic effects do not support the use of ginseng to help with postpartum contractility, but instead suggest it may be helpful in reducing inappropriate uterine contractions, such as in threatened preterm delivery. © 2014 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.
... It was evidenced that mitragynine, the main alkaloid of ketum, at the cellukar level inhibits neurotransmitter release from the nerve endings of vas deferens, partly through the blockade of neuronal Ca 2+ channels (Matsumoto et al., 2005). It is postulated that neuronal Ca 2+ channel-blocking effect of mitragynine is the main mechanism for the analgesic and several other physiological actions of mitragynine. ...
Article
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Mitragyna speciosa Korth, or better known as ketum, has long been used by traditional folk around Southeast Asia to prevent fatigue from working under hot tropical weather and as a replacement of opium, which can then cause addiction. To date, no findings have been reported of the toxic effect of ketum subchronically (28 days). Hence, the aim of this study was to investigate the toxicity of subchronic effect of standardized methanolic extract of ketum (SMEMS) in Sprague-Dawley rats. Rats were orally administered with 100, 200, and 500 mg/kg of SMEMS for 28 days. Body weights were recorded daily. They were terminated at day 28 to obtain data for hematology, biochemistry, and histopathology of the brain, liver, kidney, lung, heart, sciatic nerve, and spinal cord. The SMEMS affected body weight compared to control group. Biochemistry findings showed that liver and kidney were affected with the abnormal values in AST, creatinine, globulin, glucose, total protein, and urea. However, SMEMS produced toxic effect more to liver, kidney, and lung than other organs as observed histopathologically. The results suggested subchronic exposure of ketum is toxic to the physiology of the animals.
... Effects are dose dependent, beginning 5e10 min after using, and continuing for 1 h after exposure [45]. In addition, a variety of chemicals separated from kratom have been shown to present opioidlike activity on smooth muscle systems and in ligandbinding studies [35,54,55]. Most distinctly, many regions of the central nervous system are sensible to the external effects of these kratom originated substances and the effects can be interfered by opioid antagonists [35,40,50,54e57]. ...
Article
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Plant-based drugs of abuse are as old as recorded human history. Although traditional addictive substances, such as opium, cannabis and coca, have been controlled by the United Nations anti-drug conventions, many, if not most, natural plants with addictive or abuse liability remain elusive. Therefore, the United Nations Office on Drugs and Crime (UNODC) has warned the emerging threat from new psychoactive substances (NPS), which are mostly derived or modified from the constituents of natural origin. For example, synthetic cannabinoids and synthetic cathinones are derived from the cannabis and khat plant, respectively. In this review, we briefly discussed the chemistry, pharmacology and toxicology of five common NPS of natural origin, i.e., khat, kratom, salvia, magic mushroom and mandrake. Through the review, we hope that professionals and general public alike can pay more attention to the potential problems caused by natural NPS, and suitable control measures will be taken.
... To date, over 40 minor compounds have also been isolated from [Adkins et al., 2011]. The quantitative and qualitative differences between the minor constituents of alkaloid extract of M. speciosa grown in Thailand and Malaysia have been investigated [Takayama, 2004], with reports of the antinociceptive activity of mitragynine [Matsumoto et al., 1996a[Matsumoto et al., ,b, 1997[Matsumoto et al., , 2005Thongpradichote et al., 1998] or alkaloid extract of M. speciosa with Thai [Kumarnsit et al., 2007;Reanmongkol et al., 2007] or Malaysian origin [Mossadeq et al., 2009, Sabetghadam et al., 2010. Studies show that mitragynine exerts its pharmacological effects as an agonist of mand k-opioid receptors [Boyer et al., 2008]. ...
Article
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Mitragyna speciosa is a widely used medicinal plant that is commonly used for its morphine-like effect sin folklore medicine in Thailand and Malaysia due to its ability to reduce pain and ameliorate withdrawal signs after cessation of opioid abuse. The aim of the present study was to determine and compare the relative safety and therapeutic indices of M. speciosa alkaloid extract and its major component, mitragynine. An alkaloid extract (20–400 mg/kg) from the leaves of M. speciosa, as well as mitragynine (4.2–84 mg/kg), was orally administered to mice; dose–response relationship, ED50 and LD50 values, as well as the therapeutic index (TI), for the two substances were determined and compared with that of morphine (2.5–10 mg/kg, s.c.). The results showed a significant dose-dependent response in both extract (50 mg/kg onward) and mitragynine (10.5 mg/kg) with a higher potency of mitragynine than that of the extract. Although the LD50 for the extract (591 mg/kg) was higher than that of mitragynine (477 mg/kg), the TI for mitragynine was wider than that of the extract (21:3). The present study indicated that mitragynine is relatively safer when compared with the alkaloid extract of M. speciosa in mice.
... Inhibition of STP is contributed by application of specific blocker for all these channels at the same time (Quinlan et al., 2008). One of the biocompounds in M. speciosa Korth, mitragynine was also found to block T-and L-type Ca 2+ channel currents and reduce KCl induce Ca 2+ influx in neuroblastoma cells (Matsumoto et al., 2005). Therefore, from this study it might be hypothesized that MS extract inhibit the influx of Ca 2+ . ...
Article
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Mitragyna speciosa Korth or ketum or kratom has long been used by local people in Thailand and Malaysia to treat various types of diseases and to boost energy. There is lack of information available on the effect of M. speciosa Korth in learning and memory function, therefore this study was conducted to understand its effect using a cellular model (hippocampus). The objective of this study was to delineate the effect of M. speciosa Korth standardized methanol extract (MS), we used extracellular recording in rat hippocampal slices in vitro. Acute hippocampal slices were prepared from 4 weeks-old male Sprague dawley rats. Field excitatory post-synaptic potentials (fEPSP) were investigated after the application of test materials in concentrations of 0.0001, 0.001, 0.005, 0.01, 0.05 and 0.1% dissolved in 0.1% DMSO. The 50% inhibitory concentration (IC50) of test material was then calculated. Superfusion of MS (all concentrations) produced irreversible fEPSP amplitude reduction with an IC 50 of 0.008%. The same concentration of MS (0.008%) prevented the induction of long-term potentiation (LTP) and induced only short-term potentiation (STP) in CA1 neurons. In the CA1 region of the hippocampus, reduced concentration-dependently glutamatergic transmission and blocked LTP at the IC50. Key words: Mitragyna speciosa Korth standardized methanol extraction (MS), extracellular recording, field excitatory post-synaptic potential (fEPSP), short-term potentiation (STP).
... The traditional Thai herbal medicine M. speciosa has long been used in Thailand for its opioid-like effects (Burkill, 1935) and as a replacement for opium (Suwanlert, 1975). We have studied the pharmacological activities of mitragynine, a major alkaloid of this herb (Watanabe et al., 1997;Matsumoto et al., 2005b), and 7-hydroxymitragynine, a main active alkaloid of this herb (Matsumoto et al., 2004(Matsumoto et al., , 2005a(Matsumoto et al., , 2006a. Recently, additional research has been performed on the opium-like effects of M. speciosa and mitragynine and the unique chemical and pharmacological properties of mitragyninerelated indole alkaloids (Adkins et al., 2011;Raffa et al., 2013). ...
Article
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7-Hydroxymitragynine, a main active constituent of the traditional herbal medicine Mitragyna speciosa, is an indole alkaloid that is structurally different from morphine. 7-Hydroxymitragynine induced a potent antinociceptive effect on mouse acute pain through μ-opioid receptors. In this study, we developed dual-acting μ- and δ-opioid agonists MGM-15 and MGM-16 from 7-hydroxymitragynine for the treatment of acute and chronic pain. MGM-16 showed a higher potency than that of 7-hydroxymitragynine and MGM-15 in vitro and in vivo assays. MGM-16 exhibited a high affinity for μ- and δ-opioid receptors with Ki values of 2.1 and 7.0 nM, respectively. MGM-16 showed a μ- and δ-opioid full agonistic effects in a [(35)S]GTPγS binding assay and in a functional test using electrically elicited guinea-pig ileum and mouse vas deferens contractions. Systemic administration of MGM-16 produced antinociceptive effects in a mouse acute pain model and anti-allodynic effects in a chronic pain model. The antinociceptive effect of MGM-16 was about 240 times more potent than that of morphine in a mouse tail-flick test and its anti-allodynic effect was about 100 times more potent than that of gabapentin in partial sciatic nerve-ligation mice, especially with oral administration. The antinociceptive effect of MGM-16 was completely and partially blocked by theμ-selective antagonist β-FNA and by the δ-selective antagonist naltrindole, respectively, in a tail-flick test. The anti-allodynic effect of MGM-16 was completely blocked by β-FNA and naltrindole in a neuropathic pain model. These findings suggest that MGM-16 could become a class of compounds with potential therapeutic utility for treating neuropathic pain.
... Three studies examined the effects on contractility of vas deferens ( shows that the inhibitory activity is probably at neuronal levels ( Matsumoto et al., 2005b). Table 2.3i shows a study examined the effect of MS on uterus and urinary bladder contractility. ...
Thesis
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Mitragyna speciosa (MS) belongs to Rubiaceae family and is a tree native to countries in South East Asia. The consumption of Mitragyna speciosa (MS) for its psychoactive effects is widely reported amongst people in the villages in Thailand and Malaysia even though its use is illegal. Yet, little is known about its properties and pattern of use. The first part of the study aimed to examine MS pharmacological properties using systematic review methodology. The second part aimed to examine the prevalence, patterns of MS use as well as explored its potential to cause dependence in a crosssectional study. For the systematic review on the pharmacological properties of MS, comprehensive literature searches were carried out for articles on MS published from inception to February 2012 with no restriction on language. Thirty-one electronic databases, including the MEDLINE, TRIPDATABASE and BIOMED CENTRAL were searched. Only animal studies examining the pharmacological properties of MS or its compound were included while studies on the pharmacokinetic, toxicology and cell studies were excluded. Two review authors independently screened potentially eligible studies and extracted the data. A total of 44 studies were included in the review. Most of the studies examined the antinociceptive effects of MS (20 studies) and contractility of smooth muscle (14 studies). Other pharmacological effects examined included effects on bioamines levels, behavioural and the anti-inflammatory effects. It appears that mitragynine and 7-hydroxymitragynine, the two active constituents of MS have antinociceptive properties and that they act through μ- and δ-supraspinal opioid receptors. iv In the cross-sectional study, we used both convenience and snowball-sampling methods to recruit participants in a border town between two northern states in Malaysia. Faceto- face interviews were conducted with the use of a structured questionnaire on 562 respondents who gave oral consent to participate in the study. The response rate was 91%. The majority of the respondents (88%) reported daily use of MS. The main mode of using MS was by drinking the MS extract as tea (90%). The mean age of starting MS use was 28.3 (SD = 8.1) years. A variety of reasons were given for using MS including for social and recreational needs, stamina and physical endurance, pain relief and improved sexual performance. Despite its reported usefulness in weaning off opiate addiction, 460 (87%) admitted they were not able to stop using MS. Only education level had a statistically significant association with the ability to stop or not stop the use of MS (2 = 31.0, df = 1, p <0.001). Significantly higher proportions of those with a lower education level (38%) were able to stop using MS compared to respondents with a higher education level (10%). The study provides important information on the pharmacological effects of MS, its pattern of use and effects and its potential to cause addiction, as there has been growing interest in MS as evidenced by the number of advertisements for its sale on the Internet. Future study is required to explore its psychological and social impact on users
... Recently, the pharmacological properties of various MS extracts or mitragynine have been broadly evaluated. Many studies were performed on the antinociceptive effects of MS extracts and mitragynine in appropriate animal model (Macko et al., 1972;Matsumoto et al., 1996aMatsumoto et al., , 1996bTohda et al.,1997;Watanabe et al., 1997;Idid et al., 1998;Thongpradichote et al., 1998;Matsumoto et al., 2005;Horie et al., 2005;Reanmongkol et al., 2007;Sabetghadam et al., 2010). MS extracts or mitragynine were also reported to have anti-inflammatory (Mossadeq et al., 2009;Utar et al., 2011) and anti-depressant-like (Kumarnsit et al., 2007b;Farah Idayu et al., 2010) properties in animal models. ...
... Meanwhile, the sedative opium-like effects were experienced if consumed at large doses and this can be used to treat pain and opium withdrawal (Boyer et al., 2008;Wray, 1907aWray, , 1907b. Till present, scientific research has only communicated mainly on the anaesthetic, antitussive, stimulant and opioid properties of M. speciosa (Horie et al., 2005;Matsumoto et al., 2006Matsumoto et al., , 2004Matsumoto et al., , 2005aMatsumoto et al., , 2005bTakayama, 2004;Takayama et al., 2002Takayama et al., , 2006Watanabe et al., 1997;Yamamoto et al., 1999). Such pharmacological activities were often attributed to the alkaloid contents of the leaf and were obtained through conventional solvent extraction using dichloromethane or methanol. ...
Article
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Mitragyna speciosa Korth., is a controversial plant that possesses various medicinal values and has been used from time immemorial in folk medicine. Recently, it has been widely abused as a narcotic source. The aim of the present study was to characterize the in vitro nitric oxide (NO) inhibition property of the supercritical CO 2 fluid extracts from M. speciosa leaves and to identify the chemical constituents of the extract that exhibited the most inhibition without toxicity effect. Samples were extracted using the green technology, supercritical fluid extraction (SFE) technique via CO 2 as the mobile phase. The NO inhibitory activity was evaluated by Griess assay, which measures the formation of nitrite ion (NO 2 À) in recombinant mouse interferon gamma/lipopolysaccharide (IFN-c/ LPS) stimulated RAW 264.7 cells. Matrix 5 Step-1 (M5S1) that was extracted with pure CO 2 at 3000 psi and 60 °C exhibited the highest NO inhibitory activity (60.08%) without cytotoxicity (cell viability, 91.98%) at a concentration of 100 lg/mL. GC and GC–MS analysis revealed palmitic acid as the major constituent (34.90%) of M5S1. This study provides first evidence that M5S1, the non-alkaloidal extract obtained by supercritical fluid extraction of M. speciosa leaves possesses potential property in preventing inflammatory diseases mediated by excessive production of NO.
... The central monoaminergic system was shown to be involved in the pain modulation activity of mitragynine. The noxious stimulus test showed the descending noradrenergic and serotonergic systems modulates the anti-nociceptive activity of mitragynine on tail flick test (mechanical stimulation) while the descending noradrenergic system regulates the anti-nociceptive activity of mitragynine hot-plate test (thermal stimulation) [19] . The mitragynine suppression of head twitch response caused by 5-methoxy-N,N-dimethyltryptamine demonstrated the effect of mitragynine on serotonergic function in the brain [20] . ...
... Users report that the dominant effects are similar to those of psychostimulant drugs (4). The possible analgesic ability of mitragynine is linked to its interaction with supraspinal μand δ-receptors (5), and its possible stimulant activity may be due to the blocking of the stimulation of serotonergic 5-HT2A receptors and to the postsynaptic stimulation of the α-2 adrenergic receptors (6). There is a growing concern for abuse and dependence. ...
Article
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Background Kratom (Mitragyna speciosa) is a tropical tree with a long history of traditional use in parts of Africa and Southeast Asia. Kratom is also known as Thom, Thang, and Biak. Its leaves and the teas brewed from them have long been used by people in that region to manage pain and opioid withdrawal and to stave off fatigue. Kratom is actually consumed throughout the world for its stimulant effects and as an opioid substitute (in form of tea, chewed, smoked, or ingested in capsules). Some case reports have associated kratom exposure with psychosis, seizures, intrahepatic cholestasis, other medical conditions, and deaths. The clinical manifestations of kratom effects are not well defined and the clinical studies are limited. Data research suggest that both stimulant and sedative dose-dependent effects do exist, in addition to antinociceptive, antidepressant activity, anxiolytic-like effects, and anorectic effects, but a growing concern for the drug’s effects and safety of use has resulted in national and international attention primarily due to an increase in hospital visits and deaths in several countries that are believed to have been caused by extracts of the plant. There is a dearth of double blind controlled studies. In this study, we aim to use existing literature to clarify both benefits and risks of kratom as well as its diagnosis evaluation as kratom misuse is an emerging trend in the Western world.Methods Literature review using databases such as Embase, Medline, PubMed, Cochrane Library, and Mendeley from 2007 to 2017 were evaluated by all authors to analyze current state on benefits, risks, and diagnosis evaluation of kratom (M. speciosa).ResultsData analysis suggested that kratom possesses some benefits such as stimulant and sedative effects as wells as antinociceptive effects. It seems to inhibit pro-inflammatory mediator release and vascular permeability and can enhance immunity. In addition, it may be an antidepressant and anorectic. However, kratom can cause intrahepatic cholestasis, seizure, arrhythmia, impair memory function, coma, and death. Psychological manifestations described are euphoria and feeling relaxed to severe symptoms such as aggression, hostility, and psychosis. Medical manifestations described are polyuria, dry mouth, vomiting, and jerky movements. Currently, liquid chromatography/mass spectrometry and ion mobility spectrometry (IMS) are suggested as the most promising to rapidly screen kratom products providing a positive success rate.Conclusion Our data analysis has not determined if biochemical benefits of kratom may prove to outweigh its toxicity and risks. On the contrary, it seems that its potential side effects outweigh the benefits, and severe and real health hazards can, insidiously, lead to death. Kratom clinical, psychological, and medical manifestations can be disturbing. Kratom (M. speciosa) use, among multiple compounds of the leaf, appear to be increasing in the Western world. Promising methods to accurately identify kratom compounds are still ongoing.
... Owing to this biased G-protein opioid activity, mitragynine produces antinociception through µ-opioid receptors (EC 50 , 203 ± 13 nM) without recruiting β-arrestin-2 proteins and their putative associated side effects (e.g., respiratory depression, constipation, physical dependence, and tolerance), unlike morphine and β-endorphin [10,11]. Mitragynine inhibits forskolin-stimulated 3′,5′-cyclic adenosine monophosphate (cAMP) formation along with the blocking of opioid receptor-mediated neuronal Ca 2+ release on the cellular level [12,13]. Both of these mitragynine-mediated cellular effects are considered potential mechanisms in the central nervous system-mediated analgesic and behavioral effects. ...
Article
Kratom (Mitragyna speciosa) has been examined for its opioid activity, especially for the treatment of opioid withdrawal and pain. Mitragynine, the most abundant alkaloid in kratom, is thought to be the major psychoactive alkaloid. An HPLC method was developed for the quantification of mitragynine in kratom leaf extracts. In addition, a multiple reaction mode based UPLC-MS/MS method was developed and validated for the quantification of mitragynine in rat plasma. Pharmacokinetic studies were performed by comparing a single intravenous dose of mitragynine (5 mg/kg, mitragynine hydrochloride) to a single oral dose of mitragynine (20 mg/kg, mitragynine hydrochloride), lyophilized kratom tea, and the organic fraction of the lyophilized kratom tea at an equivalent mitragynine dose of 20 mg/kg in rats. After intravenous administration, mitragynine exhibited a biexponential decrease in the concentration-time profile, indicating the fast distribution of mitragynine from the systemic circulation or central compartment to the peripheral compartments. Mitragynine hydrochloride, lyophilized kratom tea, and the lyophilized kratom tea organic fraction were dosed orally and the absolute oral bioavailability of mitragynine in rats was found to be 1.5- and 1.8-fold higher than that of mitragynine dosed alone. The results provide evidence that an equivalent oral dose of the traditional preparation (lyophilized kratom tea) and formulated/manufactured products (organic fraction) of kratom leaves provide better systemic exposure of mitragynine than that of mitragynine dosed alone.
... Other compounds have been isolated from M. speciosa and reported to have pharmaceutical applications including rhynchophylline (noncompetitive N-methyl-D-aspartate receptor antagonist), speciophylline, speciogynine (smooth muscle relaxer), and paynatheine (stimulant) (Figure 1; Shellard et al. 1978). These compounds have been shown to modulate intestinal smooth muscle function and behavioral response in animals (Matsumoto et al. 2005). ...
Article
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Mitragyna speciosa (kratom) produces numerous compounds with pharmaceutical properties including the production of bioactive monoterpene indole and oxindole alkaloids. Using a linked-read approach, a 1,122,519,462 bp draft assembly of M. speciosa ‘Rifat’ was generated with an N50 scaffold size of 1,020,971 bp and an N50 contig size of 70,448 bp that encodes 55,746 genes. Chromosome counting revealed that ‘Rifat’ is a tetraploid with a base chromosome number of 11, which was further corroborated by orthology and syntenic analysis of the genome. Analysis of genes and clusters involved in specialized metabolism revealed genes putatively involved in alkaloid biosynthesis. Access to the genome of M. speciosa will facilitate an improved understanding of alkaloid biosynthesis and accelerate production of bioactive alkaloids in heterologous hosts.
... In addition to these, mitragynine binds to δ-opioid receptors, thereby exercising analgesic effects [3,50]. Mitragynine is able to block Ca 2+ channels, affecting the release of neurotransmitters [115,116]. Thus, antidepressant, antioxidant and anti-inflammatory properties have been associated with kratom consumption [117,118]. The use of this substance for substitution treatment in chronic opioid users has also been reported [3,50]. ...
Article
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The consumption of new psychoactive substances (NPSs) has been increasing, and this problem affects several countries worldwide. There is a class of NPSs of natural origin, consisting of plants and fungi, which have a wide range of alkaloids, responsible for causing relaxing, stimulating or hallucinogenic effects. The consumption of some of these substances is prompted by religious beliefs and cultural reasons, making the legislation very variable or even ambiguous. However, the abusive consumption of these substances can present an enormous risk to the health of the individuals, since their metabolism and effects are not yet fully known. Additionally, NPSs are widely spread over the internet, and their appearance is very fast, which requires the development of sophisticated analytical methodologies, capable of detecting these compounds. Thus, the objective of this work is to review the toxicological aspects, traditional use/therapeutic potential and the analytical methods developed in biological matrices in twelve plant specimens (Areca catechu, Argyreia nervosa, Ayahuasca, Catha edulis, Datura stramonium, Lophophora williamsii, Mandragora officinarum, Mitragyna speciosa, Piper methysticum Forst, Psilocybe, Salvia divinorum and Tabernanthe iboga).
... Among the alkaloids in kratom leaves, mitragynine is the major indole alkaloid accounting for up to 66% (Takayama 2004). Mitragynine exerts several pharmacological activities including analgesia (Matsumoto et al. 1996), ileal relaxation (Watanabe et al. 1997), inhibiting gastric secretion (Tsuchiya et al. 2002), stimulation of the CNS (Matsumoto et al. 2005), anti-depression (Idayu et al. 2011), and anti-inflammation (Utar et al. 2011). Mitragynine acts as a partial agonist of µ-opioid receptors and as a competitive antagonist of the κ-and δ-opioid receptors. ...
Article
Mitragynine is a major psychoactive alkaloid in leaves of kratom (Mitragyna speciosa Korth.). To understand its disposition in organs, this study aimed to develop a physiologically based pharmacokinetic (PBPK) model that predicts mitragynine concentrations in plasma and organ of interests in rats and humans. The PBPK model consisted of six organ compartments (i.e. lung, brain, liver, fat, slowly perfused tissues, and rapidly perfused tissue). From systematic searching, three pharmacokinetic studies of mitragynine (two studies in rats and 1 study in humans) were retrieved from the literature. Berkeley Madonna Software (version 8.3.18) was used for model development and model simulation. The developed PBPK model consisted of biologically relevant features following involvement of (i) breast cancer-resistant protein (BCRP) in brain, (ii) a hepatic cytochrome P450 3A4 (CYP3A4)-mediated metabolism in the liver, and (iii) a diffusion-limited transport in fat. The simulations adequately describe simulated and observed data in the two species with different dosing regimens. PBPK models of mitragynine in rats and humans were successfully developed. The models may be used to guide optimal mitragynine dosing regimens.
... It acts as a receptor agonist at μ-opioid receptors and possibly as an antagonist at κ-opioid receptors [28], [29], [30]. At cellular level, MG blocks neuronal Ca 2+ channels [31]. It was also found to inhibit forskolin-stimulated cyclic adenosine monophosphate (cAMP) formation in vitro in an opiate receptor-dependent way [32], [33]. ...
Article
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Mitragyna speciosa, commonly known as Ketum or Biak in Malaysia and Kratom in Thailand, is a native plant to Southeast Asia and has various pharmacological benefits. Mitragynine (MG) is the principal alkaloid found in the leaves of Mitragyna speciosa and has been reported to be responsible for the plant’s therapeutic actions. Traditionally, local communities use Kratom preparations for relief from different types of pain. The potential analgesic effects of MG using rodent models have been reported in literatures. We have reviewed the published analgesic and pharmacokinetic studies and all of these findings showed the routes of drug administration, doses employed, and type of vehicles used to solubilize the drug, varied considerably; hence this posted difficulties in predicting the drug’s pharmacokinetic-response relationship. A rational approach is warranted for accurate prediction of dose-response relationship; as this is essential for the development of MG as an alternative medicinal drug for pain management. PKPD modeling would serve as a better method to understand the dose-response relationship in future MG preclinical and clinical studies
... However, pre-treatment with mitragynine at concentration of 10, 30, and 100 µM potently inhibited Ca 2+ influx upon glutamate stimulation, findings that corroborate previous research. For example, Matsumoto et al. (2005) showed that mitragynine blocks T-and L-type Ca 2+ channel currents and reduces KCl-induced Ca 2+ influx in neuroblastoma cells. Based on these results and on our observations of inhibition of glutamate-elicited Ca 2+ influx, one can speculate that changes in Ca 2+ signaling underlie the impairments of hippocampal transmission and plasticity, as well as of memory acquisition, seen with mitragynine administration. ...
Article
Background: Mitragynine is the major alkaloid of Mitragyna speciosa (Korth.) or Kratom, a psychoactive plant widely abused in Southeast Asia. While addictive effects of the substance are emerging, adverse cognitive effects of this drug and neuropharmacological actions are insufficiently understood. Aims: In the present study, we investigated the effects of mitragynine on spatial learning and synaptic transmission in the CA1 region of the hippocampus. Methods: Male Sprague Dawley rats received daily (for 12 days) training sessions in the Morris water maze, with each session followed by treatment either with mitragynine (1, 5, or 10 mg/kg; intraperitoneally), morphine (5 mg/kg; intraperitoneally) or a vehicle. In the second experiment, we recorded field excitatory postsynaptic potentials in the hippocampal CA1 area in anesthetized rats and assessed the effects of mitragynine on baseline synaptic transmission, paired-pulse facilitation, and long-term potentiation. Gene expression of major memory- and addiction-related genes was investigated and the effects of mitragynine on Ca2+ influx was also examined in cultured primary neurons from E16-E18 rats. Results/outcomes: Escape latency results indicate that animals treated with mitragynine displayed a slower rate of acquisition as compared to their control counterparts. Further, mitragynine treatment significantly reduced the amplitude of baseline (i.e. non-potentiated) field excitatory postsynaptic potentials and resulted in a minor suppression of long-term potentiation in CA1. Bdnf and αCaMKII mRNA expressions in the brain were not affected and Ca2+ influx elicited by glutamate application was inhibited in neurons pre-treated with mitragynine. Conclusions/interpretation: These data suggest that high doses of mitragynine (5 and 10 mg/kg) cause memory deficits, possibly via inhibition of Ca2+ influx and disruption of hippocampal synaptic transmission and long-term potentiation induction.
... There is currently no exact lethal dose known for humans. Overdoses have been reported in the setting of long-term use and exposure as well as acutely after first time ingestion [40]. ...
... At a cellular level, mitragynine can inhibit neurotransmitter release by reversibly blocking neuronal Ca 2+ channels. It is proposed by the authors that the decrease in neurotransmitters leads to inhibition of pain transduction [66]. Mitragynine also inhibited adenylyl cyclase in NG108-15 cells through opioid receptors. ...
Article
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The abuse of psychotropic substances is a well-known phenomenon, and many of them are usually associated with ancestral traditions and home remedies. This is the case of Mitragyna speciosa (kratom), a tropical tree used to improve work performance and to withstand great heat. According to several published studies, the main reasons for kratom consumption involve improving sexual performance and endurance, but also social and recreational uses for the feeling of happiness and euphoria; it is also used for medical purposes as a pain reliever, and in the treatment of diarrhea, fever, diabetes, and hypertension. However, this plant has gained more popularity amongst young people over the last years. Since it is available on the internet for purchase, its use is now widely as a drug of abuse, namely as a new psychoactive substance, being a cheaper alternative to opioids that does not require medical prescription in most countries. According to internet surveys by the European Monitoring Centre for Drugs and Drug Addiction in 2008 and 2011, kratom was one of the most widely supplied new psychoactive substances. The composition of kratom is complex; in fact, more than 40 different alkaloids have been identified in Mitragyna speciosa so far, the major constituent being mitragynine, which is exclusive to this plant. Besides mitragynine, alkaloids such as corynantheidine and 7-hydroxamitragynine also present pharmacological effects, a feature that may be attributed to the remaining constituents as well. The main goal of this review is not only to understand the origin, chemistry, consumption, and analytical methodologies for analysis and mechanism of action, but also the use of secondary metabolites of kratom as therapeutic drugs and the assessment of potential risks associated with its consumption, in order to aid health professionals, toxicologists, and police authorities in cases where this plant is present.
... Kratom extracts and mitragynine have displayed cytotoxicity to certain human cancer cell lines (e.g., SH-SY5Y) [77]. Mitragynine may modulate muscle neurogenic contraction [78][79][80], and gastric secretion [81], consistent with traditional use. There are also anecdotal reports that it has aphrodisiac properties [9]. ...
... Krathom constituents act on the central nervous system as both a psycho-stimulant and depressant. They comprise over 25 alkaloids with mitragynine being dominant and acting as a stimulant, and 7-hydroxymitragynine having sedating effects (Chittrakarn, Keawpradub, Sawangjaroen, Kansenalak, & Janchawee, 2010;Matsumoto et al., 2005). ...
Article
Background: Krathom is currently the most popular illicit substance in use in southern Thailand. Research regarding its effects and health impacts is scarce. This study explored the pattern of krathom use and users' perceptions of the consequences of its use. Methods: An in-depth qualitative interview. A group of 34 self-identified regular users, occasional users, non-users and ex-users of krathom was used in this study. Health volunteer as a key-contact person helped the researcher to invite villagers to participate in the study using snowballing technique. The process of data analysis was guided by Strauss and Corbin's grounded theory. Results: The core category, 'Understanding krathom use', was generated from three inter-related categories: (i) reasons for continuing krathom use, (ii) the way of applying krathom, and (iii) perceiving positive and realizing the negative effects of krathom use and their 18 subcategories. Conclusions: The study findings reveal the importance of considering krathom use from the perspective and belief of the villagers. Krathom is addictive with its own characteristic symptoms and signs. The results provide support for policy interventions to control the availability of krathom according to the community context. In addition, krathom misuse by adolescents must be considered.
... The plant has also been used as self-medication for opiate and alcohol withdrawal (Boyer et al., 2008;Havemann-Reinecke, 2011). Actions of kratom in the central nervous system, which involve interaction with opioid receptors, descending monoaminergic projections, and neuronal Ca 2 ⁺ channels ( Matsumoto et al., 2005), might explain, at least in part, its effectiveness in reducing withdrawal symptoms. ...
Article
Ethnopharmacological relevance: Mitragyna speciosa and its extracts are called kratom (dried leaves, extract). They contain several alkaloids with an affinity for different opioid receptors. They are used in traditional medicine for the treatment of different diseases, as a substitute by opiate addicts, and to mitigate opioid withdrawal symptoms. Apart from their medical properties, they are used to enhance physical endurance and as a means of overcoming stress. Purpose: The aim of this study was to determine the mechanisms underlying the effects of kratom on restraint-stress-induced analgesia which occurs during or following exposure to a stressful or fearful stimulus. Methods: To gain further insights into the action of kratom on stress, we conducted experiments using restraint stress as a test system and stress-induced analgesia as a test parameter. Using transgenic mu opioid-receptor (MOR) deficient mice, we studied the involvement of this receptor type. We used nor-binaltorphimine (BNT), an antagonist at kappa opioid receptors (KOR), to study functions of this type of receptor. Membrane potential assay was also employed to measure the intrinsic activity of kratom in comparison to U50,488, a highly selective kappa agonist. Results: Treatment with kratom diminished stress-induced analgesia in wildtype and MOR knockout animals. Pretreatment of MOR deficient mice with BNT resulted in similar effects. In comparison to U50,488, kratom exhibited negligible intrinsic activity at KOR alone. Conclusions: The results suggest that the use of kratom as a pharmacological tool to mitigate withdrawal symptoms is related to its action on KOR.
... It acts as a receptor agonist at μ-opioid receptors and possibly as an antagonist at κ-opioid receptors (56, [69][70][71]. At cellular level, mitragynine blocks neuronal Ca 2+ channels (72). It was also found to inhibit forskolin-stimulated cyclic adenosine monophosphate (cAMP) formation in vitro in an opiate receptor-dependent way (73,74). ...
Article
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A feature of human culture is that we can learn to consume chemical compounds, derived from natural plants or synthetic fabrication, for their psychoactive effects. These drugs change the mental state and/or the behavioral performance of an individual and can be instrumentalized for various purposes. After the emergence of a novel psychoactive substance (NPS) and a period of experimental consumption, personal and medical benefits and harm potential of the NPS can be estimated on evidence base. This may lead to a legal classification of the NPS, which may range from limited medical use, controlled availability up to a complete ban of the drug form publically accepted use. With these measures, however, a drug does not disappear, but frequently continues to be used, which eventually allows an even better estimate of the drug’s properties. Thus, only in rare cases, there is a final verdict that is no more questioned. Instead, the view on a drug can change from tolerable to harmful but may also involve the new establishment of a desired medical application to a previously harmful drug. Here, we provide a summary review on a number of NPS for which the neuropharmacological evaluation has made important progress in recent years. They include mitragynine (“Kratom”), synthetic cannabinoids (e.g., “Spice”), dimethyltryptamine and novel serotonergic hallucinogens, the cathinones mephedrone and methylone, ketamine and novel dissociative drugs, γ-hydroxybutyrate, γ-butyrolactone, and 1,4-butanediol. This review shows not only emerging harm potentials but also some potential medical applications.
Article
Kratom use is a growing problem in the United States. Kratom exposures reported to Texas poison centers between January 1998 and September 2013 were identified. No kratom exposures were reported from 1998 to 2008 and 14 exposures were reported from 2009 to September 2013. Eleven patients were male, and 11 patients were in their 20s. The kratom was ingested in 12 patients, inhaled in 1, and both ingested and inhaled in 1. Twelve patients were managed at a healthcare facility and the remaining 2 were managed at home.
Article
CYP450 enzymes are key determinants in drug toxicities, reduced pharmacological effect and adverse drug reactions. Mitragynine, an euphoric compound was evaluated for its effects on the expression of mRNAs encoding CYP1A2, CYP2D6 and CYP3A4 and protein expression and resultant enzymatic activity. The mRNA and protein expression of CYP450 isoforms were carried out using an optimized multiplex qRT-PCR assay and Western blot analysis. CYP1A2 and CYP3A4 enzyme activities were evaluated using P450-Glo(™) assays. The effects of mitragynine on human CYP3A4 protein expression were determined using an optimized hCYP3A4-HepG2 cell-based assay. An in silico computational method to predict the binding conformation of mitragynine to the active site of the CYP3A4 enzyme was performed and further validated using in vitro CYP3A4 inhibition assays. Mitragynine was found to induce mRNA and protein expression of CYP1A2. For the highest concentration of 25 μM, induction of mRNA was approximately 70% that of the positive control and was consistent with the increased CYP1A2 enzymatic activity. Thus, mitragynine is a significant in vitro CYP1A2 inducer. However, it appeared to be a weak CYP3A4 inducer at the transcriptional level and a weak CYP3A4 enzyme inhibitor. It is therefore, unlikely to have any significant clinical effects on CYP3A4 activity.
Article
Natural products found in Mitragyna speciosa, commonly known as kratom, represent diverse scaffolds (indole, indolenine, and spiro pseudoindoxyl) with opioid activity, providing opportunities to better understand opioid pharmacology. Herein, we report the pharmacology and SAR studies both in vitro and in vivo of mitragynine pseudoindoxyl (3), an oxidative rearrangement product of the corynanthe alkaloid mitragynine. 3 and its corresponding corynantheidine analogs show promise as potent analgesics with a mechanism of action that includes mu opioid receptor agonism/delta opioid receptor antagonism. In vitro, 3 and its analogs were potent agonists in [³⁵S]GTPγS assays at the mu opioid receptor but failed to recruit β-arrestin-2, which is associated with opioid side effects. Additionally, 3 developed analgesic tolerance more slowly than morphine, showed limited physical dependence, respiratory depression, constipation, and displayed no reward or aversion in CPP/CPA assays, suggesting that analogs might represent a promising new generation of novel pain relievers.
Article
Fe, Co, or Ni as a promoter was added into the Ag/SiO2 catalyst for the vapor-phase synthesis of 3-methylindole from aniline and 1,2-propanediol. The promoted Ag/SiO2 catalysts were characterized by X-ray diffraction, H2 temperature-programmed reduction, and ther- mogravimetry. The results indicated that the addition of Fe or Ni to Ag/SiO2 was favorable for the increase of the catalyst selectivity. Among them, Fe could reinforce the interaction between the silver active component and the support and greatly promote the dispersion of silver particles on the support, which resulted in the remarkable increase in the initial activity of the catalyst. Adding Co or Ni to Ag/SiO2 promoted the sintering of silver during the reaction although it reduced the coking a little. As a result, the stability of the catalysts decreased.
Chapter
This chapter describes the pharmacology, clinical effects and toxicology of naturally occurring tryptamines (including dimethyltryptamine and mitragynine), and synthetic tryptamines (unsubstituted, 4-substituted and 5-substituted). A description of the diverse pharmacokinetic properties of tryptamines is followed by a review of receptor interactions, particularly serotonin receptor agonism responsible for hallucinogenic psychoactive effects. User reports detailing desired effects of tryptamines are reviewed. The chapter describes prevalence data demonstrating increasing use of synthetic tryptamines in the developed world, and the use of naturally occurring tryptamines including mitragynine outside of traditional settings. Animal and human experimental data demonstrating tryptamine toxicity is reviewed, followed by a summary of user reports describing unwanted effects. The chapter concludes by reviewing deaths associated with tryptamine exposure including deaths associated with the increasing use of mitragynine.
Article
Kratom, or Mitragyna, is a tropical plant indigenous to Southeast Asia, with unique pharmacological properties. It is commonly consumed by preparing the leaves into decoction or tea, or by grinding them into a powder. Recent evidence has revealed that kratom has physiological effects similar to opioids, including pain relief and euphoria, as well as stimulant properties, which together raise potential concern for dependence and addiction. Moreover, growing evidence suggests that the prevalence of kratom use is increasing in many parts of the world, raising important considerations for healthcare providers. This manuscript will discuss the most current epidemiology, pharmacology, toxicity, and management related to kratom, while seeking to provide a contemporary perspective on the issue and its role in the greater context of the opioid epidemic.
Chapter
Plants are an important source of biomolecules widely used in medical treatments, and among such products, the alkaloids are a very interesting and complex group. The definition of the term “alkaloid” is still a cause of controversy due to the similarity of some of these natural molecules with other secondary compounds. From a biological point of view, alkaloids are a group of chemicals actively involved in different biological processes of plants, animals, and microorganisms at different cellular levels. In medical science alkaloids are nitrogenous compounds, derived from vegetables origin, characterized by high molecular masses and complex structures. A possible classification of alkaloids is based on their biological and ecological activity, chemical structures, and biosynthetic pathway. They are grouped according to the shape and origins, and in this view three main groups of alkaloids can be distinguished: true alkaloids, protoalkaloids, and pseudoalkaloids.
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The use of substances to enhance human abilities is a constant and cross-cultural feature in the evolution of humanity. Although much has changed over time, the availability on the Internet, often supported by misleading marketing strategies, has made their use even more likely and risky. This paper will explore the case of Mitragyna speciosa Korth. (kratom), a tropical tree used traditionally to combat fatigue and improve work productivity among farm populations in Southeast Asia, which has recently become popular as novel psychoactive substance in Western countries. Specifically, it (i) reviews the state of the art on kratom pharmacology and identification; (ii) provides a comprehensive overview of kratom use cross-culturally; (iii) explores the subjective experiences of users; (iv) identifies potential risks and side-effects related to its consumption. Finally, it concludes that the use of kratom is not negligible, especially for self-medication, and more clinical, pharmacological, and socioanthropological studies as well as a better international collaboration are needed to tackle this marginally explored phenomenon.
Article
Kratom is an herbal product commonly used for its effects which are similar to opioids and stimulants. Few studies demonstrate the dangers and lethality of Kratom, and most fatalities from Kratom involve other abused substances. In the current case report, a 33‐year‐old white man with a known history of opioid abuse and mental illnesses was found unresponsive in his basement with no obvious signs of trauma. After resuscitative efforts, he was pronounced dead and taken for autopsy evaluation. Blood from the inferior vena cava was analyzed for common abused substances. The laboratory toxicology work‐up revealed positive findings of caffeine, cotinine, and naloxone with low levels of Δ‐9 tetrahydrocannabinol. However, a marked level of mitragynine at 1.9 mg/L was observed, the highest reported to date. Given the facts and evidence, the medical examiner certified the cause of death as “mitragynine toxicity” and the manner of death was classified as an “accident.”
Article
Mitragynine is the main psychoactive ingredient of the herbal drug preparation Kratom (Ketum), derived from the plant Mitragyna speciosa. Kratom is a widely abused drug in Southeast Asian and has a psychostimulant profile at low-medium doses, while high doses have opioidergic effects. Mitragynine was shown to possess opiate receptor affinity. However, its role in the behavioural effects of mitragynine is unclear. Here we asked whether the reinforcing effects of mitragynine are mediated by opiate receptors using a conditioned place preference (CPP) paradigm in rats. In the first experiment we tested the effects of the opiate receptor antagonist naloxone (0.1, 0.3 and 1.0 mg/kg) on the acquisition of mitragynine (10 mg/kg)-induced CPP. In the second experiment, we tested the involvement of opiate receptors in the expression of mitragynine-induced CPP in rats. We found that naloxone suppresses the acquisition of mitragynine-induced CPP. This effect was already evident at a dose of naloxone (0.1 mg/kg) which, by itself, had no conditioned place aversion (CPA) effect. Higher doses of naloxone induced a CPA and blocked mitragynine-induced CPP. In contrast, naloxone had no effect on the expression of mitragynine-induced CPP. These findings suggest that the acquisition, but not the expression of the reinforcing effects of mitragynine is mediated by opiate receptors.
Article
Ethnopharmacological relevance: The genus Mitragyna (Rubiacaeae) has been traditionally used in parts of Africa, Asia and Oceania. In recent years, there has been increased interest in species of Mitragyna with the introduction of products to western markets and regulatory uncertainty. Aim of the study: This paper reviewed the traditional ethnomedicinal uses of leaves for species belonging to the genus Mitragyna with reference to the botany and known chemistry in order to highlight areas of interest for products currently being sold as kratom. Materials and methods: A literature search was conducted using Web of Science, Google Scholar, the Royal Museum for Central Africa, Internet Archive, Hathi Trust, and Biodiversity Heritage Library search engines in the spring of 2015, fall of 2016 and winter of 2017 to document uses of bark, leaf and root material. Results: Leaves of M. speciosa (kratom) had the most common documented ethnomedicinal uses as an opium substitute or remedy for addiction. Other species of Mitragyna were reportedly used for treating pain, however the mode of preparation was most often cited as topical application. Other uses of Mitragyna included treatment of fever, skin infections, and as a mild anxiolytic. Conclusions: Mitragyna species have been used medicinally in various parts of the world and that there is significant traditional evidence of use. Modern products that include formulations as topical application of liniments, balms or tinctures may provide effective alternatives for treatment of certain types of pains. Future research is required to establish safety and toxicology limits, medicinal chemistry parameters and the potential for different physiological responses among varying genetic populations to support regulatory requirements for Mitragyna spp.
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Despite its wide range and availability over the Internet, many emerging abuse drugs remain unknown to many doctors and health professionals. Herbal marijuana alternatives (also known as synthetic marijuana), such as K2 or ‘spice’, are a group of herbal mixtures containing vegetable matter in addition to synthetic cannabinoids. Kratom is a plant product derived from Mitragyna speciosa Korth that has similar effects to opioids, and is used for the treatment of chronic pain and alleviating the symptoms of opioid withdrawal. Salvia divinorum is a hallucinogenic drug with a therapeutic potential, but has been banned in many states due to concerns about its psychiatric effects. Methoxetamine has recently become the “legal ketamine” available over the Internet. In addition, piperazine derivatives, a class similar to amphetamine including BZP and TMFPP compounds have emerged as a legal version of “ecstasy” All these psychoactive compounds are perceived as safe drugs for people and are available online. Unfortunately, these drugs have side effects depending on the dose and the mixture of drugs with health effects ranging from slight to serious. This article reviews the pharmacology, clinical effects, toxicity and managing of these drugs.
Article
The intestinal permeability of mitragynine was investigated in situ using a single pass intestinal perfusion (SPIP) absorption model, in small intestine of rat using mitragynine in the absence/presence of the permeability markers, P-gp and/or CYP3A4 inhibitors. Mitragynine demonstrated high intestinal permeability (Peff of 1.11 × 10⁻⁴ cm/s) that is in the range of highly permeable drugs such as propranolol (Peff of 1.27 × 10⁻⁴ cm/s) indicating that it readily crosses the intestine. The addition of azithromycin (P-glycoprotein inhibitor) and ciprofloxacin (CYP3A4 inhibitor) or combination of both has no effect on intestinal permeability of mitragynine across the rat small intestine.
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A new family of highly fluorescent indicators has been synthesized for biochemical studies of the physiological role of cytosolic free Ca2+. The compounds combine an 8-coordinate tetracarboxylate chelating site with stilbene chromophores. Incorporation of the ethylenic linkage of the stilbene into a heterocyclic ring enhances the quantum efficiency and photochemical stability of the fluorophore. Compared to their widely used predecessor, “quin2”, the new dyes offer up to 30-fold brighter fluorescence, major changes in wavelength not just intensity upon Ca2+ binding, slightly lower affinities for Ca2+, slightly longer wavelengths of excitation, and considerably improved selectivity for Ca2+ over other divalent cations. These properties, particularly the wavelength sensitivity to Ca2+, should make these dyes the preferred fluorescent indicators for many intracellular applications, especially in single cells, adherent cell layers, or bulk tissues.
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A new family of highly fluorescent indicators has been synthesized for biochemical studies of the physiological role of cytosolic free Ca2+. The compounds combine an 8-coordinate tetracarboxylate chelating site with stilbene chromophores. Incorporation of the ethylenic linkage of the stilbene into a heterocyclic ring enhances the quantum efficiency and photochemical stability of the fluorophore. Compared to their widely used predecessor, "quin2", the new dyes offer up to 30-fold brighter fluorescence, major changes in wavelength not just intensity upon Ca2+ binding, slightly lower affinities for Ca2+, slightly longer wavelengths of excitation, and considerably improved selectivity for Ca2+ over other divalent cations. These properties, particularly the wavelength sensitivity to Ca2+, should make these dyes the preferred fluorescent indicators for many intracellular applications, especially in single cells, adherent cell layers, or bulk tissues.
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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.
Article
Starting from an optically pure alcohol, (R)-(3), which was prepared by enzymatic hydrolysis of the racemic acetate (2) or enantioselective reduction of the ketone derivative (4), the chiral total synthesis of mitragynine (1), a major corynanthe-type indole alkaloid having an analgesic effect in Mitragyna speciosa, was accomplished.
Article
Kratom is indigenous to Thailand. Market gardeners, peasants and labourers often become addicted to kratom leaf use. In certain respects, kratom addiction resembles addiction to a drug with narcotic properties, except that long term kratom addicts develop a dark skin, particularly on the cheeks. The age of onset is apparently later than in heroin addiction, and females are rare amongst those who use the substance. There were 5 cases of kratom addiction revealing psychotic symptoms; these had been seen by the author in the last yr (1974) in the outpatient department. Initially, 3 cases were suspected of having kratom psychosis of the basis of their history of addiction and their general appearance and on psychiatric examination. The measure chosen by lar to control kratom addiction by banning the cultivation of the tree has not been found to be effective, since it is a local law It is hoped that drug education for the rural youth in areas where kratom can be grown will be a more effective step towards its control.
Article
The effects of hirsutine, an indole alkaloid from Uncaria rhynchophylla (MIQ.) Jackson, on cytosolic Ca2+ level ([Ca2+]cyt) were studied by using fura-2-Ca2+ fluorescence in smooth muscle of the isolated rat aorta. Noradrenaline and high K+ solution produced a sustained increase in [Ca2+]cyt. Application of hirsutine after the increases in [Ca2+]cyt induced by noradrenaline and high K+ notably decreased [Ca2+]cyt, suggesting that hirsutine inhibits Ca2+ influx mainly through a voltage-dependent Ca2+ channel. Furthermore, the effect of hirsutine on intracellular Ca2+ store was studied by using contractile responses to caffeine under the Ca(2+)-free nutrient condition in the rat aorta. When hirsutine was added at 30 microM before caffeine treatment, the agent slightly but significantly reduced the caffeine-induced contraction. When added during Ca2+ loading, hirsutine definitely augmented the contractile response to caffeine. These results suggest that hirsutine inhibits Ca2+ release from the Ca2+ store and increases Ca2+ uptake into the Ca2+ store, leading to a reduction of intracellular Ca2+ level. It is concluded that hirsutine reduces intracellular Ca2+ level through its effect on the Ca2+ store as well as through its effect on the voltage-dependent Ca2+ channel.
Article
The effect of an active synthetic N-terminal fragment of bovine parathyroid hormone (bPTH), bPTH-(1-34), on Ca2+ channels was studied in mouse neuroblastoma cells (N1E-115). With the whole-cell variation of the patch-clamp technique, T (transient) and L (long-lasting) types of Ca2+ currents were identified. Pharmacological characterization showed that the L current was amplified by the Ca2+ channel stimulator BAY K-8644, but the T current was unaffected. The administration of bPTH-(1-34) produced dose-related inhibition of the L current, which could be reversed by BAY K-8644. The peptide had no effect on the T current. In addition, use of the fluorescent indicator fura-2 showed that bPTH-(1-34) inhibited the KCl-stimulated increase in intracellular free Ca2+ in neuroblastoma cells with L channels but not in cells with T channels. An inactivated (oxidized) preparation of bPTH-(1-34) failed to affect the L current. High-affinity binding of labeled PTH analog to these neuroblastoma cells was also demonstrated. In addition, bPTH-(1-34) inhibited the L current in cultured vascular smooth muscle cells from rat tail artery. These data indicate that, in some tissues, PTH can act as an endogenous blocker of Ca2+ entry.
Article
Ca2+ channel blocking activity of hirsutine and its pharmacological features were studied. Hirsutine (10(-6) to 3 x 10(-5) M) produced a dose-dependent relaxation of the isolated rat aorta contracted by norepinephrine and high K+ concentration. This effect was exhibited in the aorta strips with or without the endothelium, suggesting an involvement of vasodilative mechanisms not dependent on the endothelium. Hirsutine also inhibited the contractions induced by serotonin and Ca2+ channel activator YC-170, but not by Ca2+ ionophore A23187. The pA2 value of hirsutine was 6.6 +/- 0.1 (mean +/- S.E.; n = 4) in antagonizing cumulative dose-response curve for Ca2+ in the depolarized aorta strips. It is concluded that hirsutine apparently exhibits Ca2+ channel blocking activity mainly through inhibition of the voltage-dependent Ca2+ influx.
Article
A differential response to cholinomimetic agonists in epididymal and prostatic portions of rat vas deferens was characterized. The prostatic portion was less sensitive to acetylcholine and carbachol than the epididymal portion. The contraction induced by cholinomimetic agonists was inhibited in the epididymal portion by atropine (1.0-3.0 nM) and in the prostatic portion by hexamethonium (0.1 mM). The contractile response of the prostatic portion to exogenous acetylcholine was not inhibited by textrodotoxin (1.0 microM) but was attenuated by reserpine treatment (10 mg.kg-1 i.p. 24 h) and by prazosin or alpha, beta-methylene ATP. A combination of an alpha-1-adrenoceptor antagonist (prazosin) and P2 purinoceptor desensitization with alpha, beta-methylene ATP abolished the contractile response of the prostatic portion. The contraction induced by repetitive field stimulation of the prostatic portion was attenuated by hexamethonium whereas the response to a single stimulus was not modified. The data suggest that cholinomimetic drugs activate both nicotinic receptors located in nerve terminals of the prostatic portion and muscarinic receptors located in the smooth muscle cells of the epididymal portion, and that stimulation of nicotinic receptors induces the release of noradrenaline and ATP.
Article
The contractile response of the guinea pig vas deferens to motor nerve stimulation is biphasic. The first phase is antagonized by the specific adenosine triphosphate-receptor antagonist arylazido aminoproprionyl adenosine triphosphate (ANAPP3), and the second by the alpha-receptor antagonist prazosin. The underlying electrical event, the excitatory junction potential, is also blocked by ANAPP3, but not by prazosin.
1. The antinociceptive action of calcium channel blockers administered intracerebroventricularly to mice using the acetic acid writhing test was studied. 2. The drugs produced dose-dependent inhibition of the number of writhes induced by the intraperitoneal administration of 10 ml/kg of 0.6% acetic acid. 3. The CaCBs may be ranked from most to least potent as follows: verapamil > nimodipine > diltiazem > flunarizine > nifedipine > cinnarizine. 4. Since naloxone pretreatment was not able to inhibit the antinociception produced by CaCBs an opioid mechanism of action is excluded. 5. It is suggested that CaCBs can induce analgesia through a decrease in cellular Ca2+ availability, increasing the nociceptive threshold.
Article
Mitragynine is a major alkaloidal constituent extracted from the young leaves of Mitragyna speciosa Korth. (Rubiaceae). We investigated an antinociceptive activity of intraperitoneal (i.p.) and intracerebroventricular (i.c.v.) injection of this alkaloid by the tail-pinch and hot-plate tests in mice, and evaluated the mechanisms of the action using naloxone, an opioid receptor antagonist. Mitragynine (5.0-30 mg/kg, i.p. and 1.0-10 micrograms/mouse, i.c.v.) exerted a dose-dependent antinociceptive activity which was maximal at 15-45 min after injection in the tail-pinch and hot-plate tests, but it did not induce a morphine-like behavioral change. the antinociceptive actions of i.p. mitragynine were completely abolished by both s.c. (2 mg/kg) and i.c.v (10 micrograms/mouse) naloxone. The action of i.c.v. mitragynine (10 micrograms/mouse) was also antagonized by i.c.v. naloxone (10 micrograms/mouse). These results indicate that mitragynine itself can induce antinociception by acting in the brain, and that the supraspinal opioid systems are at least partly involved in the antinociceptive action of mitragynine in mice.
Article
Mitragynine is a major alkaloidal constituent of young leaves of Mitragyna speciosa Korth, that is known to exhibit narcotic-like activity. In this study, we investigated the roles of central monoaminergic systems in the antinociceptive action of mitragynine by means of the tail-pinch and hot-plate tests in mice. Mitragynine (1.0-10 micrograms) injected i.c.v. exerted a dose-dependent antinociceptive activity in both tests. The activity of mitragynine (10 micrograms, i.c.v.) in the tail-pinch test was antagonized by reserpine, 6-hydroxydopamine plus nomifensine, and p-chlorophenylalnine treatment, whereas the antinociceptive activity of morphine (3 micrograms) given i.c.v. in this test was attenuated by 6-hydroxydopamine plus nomifensine but not by p-chlorophenylalanine treatment. Moreover, the activity of i.c.v. mitragynine was also antagonized by the alpha 2-adrenoceptor antagonist, idazoxan (10 micrograms), and cyproheptadine (1 microgram) administered intrathecally (i.t.). On the other hand, the antinociceptive action of i.c.v. mitragynine (10 micrograms) in the hot-plate test was abolished by reserpine and 6-hydroxydopamine plus nomifensine, but not by p-chlorophenylalanine treatment. This action was also antagonized by i.t. injection of idazoxan (10 micrograms). These results suggest that both descending noradrenergic and serotonergic systems are involved in the antinociceptive activity of supraspinally administered mitragynine on the mechanical noxious stimulation, while the descending noradrenergic system predominantly contributes to the effect of supraspinal mitragynine on the thermal noxious stimulation. The mechanisms underlying the suppressive action of mitragynine on the nociceptive response may differ from those of morphine in mice.
Article
Mitragynine (MG), a major alkaloidal constituent extracted from the plant Mitragyna speciosa Korth, is known to exert an opioid-like activity. Our previous study showed the involvement of opioid systems in the antinociceptive activity of MG in the tail-pinch and hot-plate tests in mice. In the present study, to clarify the opioid receptor subtypes involved in the antinociceptive action of MG, we investigated the effects of selective antagonists for mu-, delta- and kappa- opioid receptors on antinociception caused by the intracerebroventricular (i.c.v.) injection of MG in the tail-pinch and hot-plate tests in mice. The coadministration of a selective mu-opioid antagonist, cyprodime (1-10 microg, i.c.v.) and the pretreatment with a selective mu1-opioid antagonist naloxonazine (1-3 microg, i.c.v.) significantly antagonized the antinociceptive activities of MG (10 microg, i.c.v.) and morphine (MOR, 3 microg, i.c.v.) in the tail-pinch and hot-plate tests. Naltrindole (1-5 ng, i.c.v.), a selective delta-opioid antagonist, also blocked the effects of MG (10 microg, i.c.v.) without affecting MOR (3 microg, i.c.v.) antinociception. Nor-binaltorphimine, a selective kappa-opioid antagonist, significantly attenuated MG (10 microg, i.c.v.) antinociception in the tail-pinch test but not in the hot-plate test at the dose (1 microg, i.c.v.) that antagonized the antinociceptive effects of the selective kappa-opioid agonist U50,488H in both tests, while it had no effect on MOR antinociception in either tests. These results suggest that antinociception caused by i.c.v. MG is dominantly mediated by mu- and delta-opioid receptor subtypes, and that the selectivity of MG for the supraspinal opioid receptor subtypes differs from that of MOR in mice.
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.
Article
Mitragynine (1) is a major alkaloidal component in the Thai traditional medicinal herb, Mitragyna speciosa, and has been proven to exhibit analgesic activity mediated by opioid receptors. By utilizing this natural product as a lead compound, synthesis of some derivatives, evaluations of the structure-activity relationship, and surveys of the intrinsic activities and potencies on opioid receptors were performed with guinea pig ileum. The affinities of some compounds for mu-, delta-, and kappa-receptors were determined in a receptor binding assay. The essential structural moieties in the Corynanthe type indole alkaloids for inducing the opioid agonistic activity were also clarified. The oxidative derivatives of mitragynine, i.e., mitragynine pseudoindoxyl (2) and 7-hydroxymitragynine (12), were found as opioid agonists with higher potency than morphine in the experiment with guinea pig ileum. In addition, 2 induced an analgesic activity in the tail flick test in mice.
Article
Mitragynine is an indole alkaloid isolated from the Thai medicinal plant Mitragyna speciosa. We previously reported the morphine-like action of mitragynine and its related compounds in the in vitro assays. In the present study, we investigated the opioid effects of 7-hydroxymitragynine, which is isolated as its novel constituent, on contraction of isolated ileum, binding of the specific ligands to opioid receptors and nociceptive stimuli in mice. In guinea-pig ileum, 7-hydroxymitragynine inhibited electrically induced contraction through the opioid receptors. Receptor-binding assays revealed that 7-hydroxymitragynine has a higher affinity for micro-opioid receptors relative to the other opioid receptors. Administration of 7-hydroxymitragynine (2.5-10 mg/kg, s.c.) induced dose-dependent antinociceptive effects in tail-flick and hot-plate tests in mice. Its effect was more potent than that of morphine in both tests. When orally administered, 7-hydroxymitragynine (5-10 mg/kg) showed potent antinociceptive activities in tail-flick and hot-plate tests. In contrast, only weak antinociception was observed in the case of oral administration of morphine at a dose of 20 mg/kg. It was found that 7-hydroxymitragynine is a novel opioid agonist that is structurally different from the other opioid agonists, and has potent analgesic activity when orally administered.
Chemistry and pharmacology of analgesic indole alkaloids from the rubiaceous plant, Mitragyna speciosa
  • Takayama