Antinociception, tolerance and withdrawal symptoms induced by 7-hydroxymitragynine, an alkaloid from the Thai medicinal herb Mitragyna speciosa

Matsumoto, Kenjiro; Horie, Syunji; Takayama, Hiromitsu; Ishikawa, Hayato; Aimi, Norio; Ponglux, Dhavadee; Murayama, Toshihiko; Watanabe, Kazuo

doi:10.1016/j.lfs.2004.10.086

Cited by 94 publications

(100 citation statements)

References 14 publications

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“…We found multiple commercial Kratom products to have concentrations of 7-hydroxymitragynine that are substantially higher than those found in raw M. speciosa leaves [16,27,30]. Our findings strongly suggest adulteration of commercial Kratom products with 7-hydroxymitragynine, a plant alkaloid with potent mu-opioid receptor activity, a practice that increases the abuse liability and addictive potential of Kratom products.…”

Section: Discussionmentioning

confidence: 59%

“…It may also contribute to problematic Kratom use, which has been reported numerous times in the literature [10,[23][24][25][26]. 7-Hydroxymitragynine's role in Kratom abuse is supported by Matsumoto et al's findings (2005), which demonstrate development of tolerance, cross-tolerance to morphine, and physical dependence in 7-hydroxymitragynine treated mice [27]. Well established is the knowledge that morphine tolerance and physical dependence are secondary to mu-opioid receptor agonism [28,29].…”

Section: Introductionmentioning

confidence: 94%

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Suspected Adulteration of Commercial Kratom Products with 7-Hydroxymitragynine

et al. 2016

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Introduction Kratom (Mitragyna speciosa), a plant native to Southeast Asia, has been used for centuries for its stimulant and opium-like effects. Mitragynine and 7-hydroxymitragynine, exclusive to M. speciosa, are the alkaloids primary responsible for Kratom's biologic and psychoactive profile, and likely contribute to its problematic use. We purchased several commercially available Kratom analogs for analysis and through our results, present evidence of probable adulteration with the highly potent and addictive plant alkaloid, 7-hydroxymitragynine. Methods A simple and sensitive LC-MS/MS method was developed for simultaneous quantification of mitragynine and 7-hydroxymitragynine in methanol extract of marketed Kratom supplements. Results We found multiple commercial Kratom products to have concentrations of 7-hydroxymitragynine that are substantially higher than those found in raw M. speciosa leaves. Conclusions We have found multiple packaged commercial Kratom products likely to contain artificially elevated concentrations of 7-hydroxymitragynine, the alkaloid responsible for M. speciosa's concerning mechanistic and side effect profile. This study describes a unique form of product adulteration, which stresses the importance of increased dietary supplement oversight of Kratom-containing supplements.

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Section: Discussionmentioning

confidence: 59%

Section: Introductionmentioning

confidence: 94%

Suspected Adulteration of Commercial Kratom Products with 7-Hydroxymitragynine

et al. 2016

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“…We have surveyed these compounds for their opioid agonistic activities in vitro to elucidate the specific structure necessary for its pharmacophore to bind to opioid receptors. A nitrogen atom, a benzene residue, and an oxygen function play a significant role in producing opioid agonistic activity (Matsumoto et al, 2005a). The conversion of an indolenine moiety in 7-hydroxymitragynine (MGM-15) and 10-fluoro-7-hydroxymitragynine into an indoline derivative (MGM-16) led to an increase in agonistic potency.…”

Section: Discussionmentioning

confidence: 99%

“…We investigated the structural similarities between morphine and 7-hydroxymitragynine using molecular modeling techniques. However, we could not superimpose all three functional groups, i.e., a nitrogen atom, a benzene residue, and an oxygen atom on the benzene ring in their structures (Matsumoto et al, 2005a). Therefore, we developed novel opioid analgesics derived from 7-hydroxymitragynine that have different pharmacophore groups from morphine that bind to m-opioid receptors.…”

Section: Introductionmentioning

confidence: 99%

Orally Active Opioid μ/δ Dual Agonist MGM-16, a Derivative of the Indole Alkaloid Mitragynine, Exhibits Potent Antiallodynic Effect on Neuropathic Pain in Mice

Matsumoto

Narita

Muramatsu

et al. 2013

J Pharmacol Exp Ther

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(E)-Methyl 2-((2S,3S,7aS,12bS)-3-ethyl-7a-hydroxy-8-methoxy-1, 2,3,4,6,7,7a,12b-octahydroindolo[2,3-a]quinolizin-2-yl)-3-methoxyacrylate (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 induces a potent antinociceptive effect on mouse acute pain through m-opioid receptors. In this study, we developed dual-acting m-and d-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 in vitro and in vivo assays. MGM-16 exhibited a high affinity for m-and d-opioid receptors, with K i values of 2.1 and 7.0 nM, respectively. MGM-16 showed m-and d-opioid full agonistic effects in a guanosine 59-O-(3-[ 35 S]thiotriphosphate) 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 antiallodynic effects in a chronic pain model. The antinociceptive effect of MGM-16 was approximately 240 times more potent than that of morphine in a mouse tail-flick test, and its antiallodynic effect was approximately 100 times more potent than that of gabapentin in partial sciatic nerve-ligated mice, especially with oral administration. The antinociceptive effect of MGM-16 was completely and partially blocked by the m-selective antagonist b-funaltrexamine hydrochloride (b-FNA) and by the d-selective antagonist naltrindole, respectively, in a tail-flick test. The antiallodynic effect of MGM-16 was completely blocked by b-FNA and naltrindole in a neuropathic pain model. These findings suggest that MGM-16 could become a class of a compound with potential therapeutic utility for treating neuropathic pain.

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“…MG is also known to exhibit almost all of the above mentioned activities of Kratom. [1][2][3] The leaf preparations contain lots of other indole-based alkaloids such as mitraphylline, speciogynine, speciociliatine and a MG metabolite 7-hydroxy-MG, whose structures closely resemble that of MG. Based on the facts that the phamacological activities of MG and its 7-hydroxy metabolite are much more potent than that of morphine 5,6) and that oral administration of MG results in a long elimination half time (3.9-6.6 h), 3,7,8) MG is thought to play a crucial role in clinical symptoms in patients who received an overdose of Kratom. Previous animal experiments concluded that a fatal risk of MG is relatively low.…”

Section: Enhancement Of Endothelial Barrier Permeability By Mitragyninementioning

confidence: 99%

Enhancement of Endothelial Barrier Permeability by Mitragynine

Matsunaga

Morikawa²,

Kamase

et al. 2017

Biological & Pharmaceutical Bulletin

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Persistent inhalation of mitragynine (MG), a major alkaloid in the leaves of Mitragyna speciosa, causes various systemic adverse effects such as seizure, diarrhea and arthralgias, but its toxicity to endothelial cells and effects on barrier function of the cells are poorly understood. In this study, we compared toxicities of MG and mitraphylline, another constituent of the leaves, against human aortic endothelial (HAE), bronchial BEAS-2B, neuronal SK-N-SH, hepatic HepG2, kidney HEK293, gastric MKN45, colon DLD1, lung A549, breast MCF7 and prostate LNCaP cells, and found that MG, but not mitraphylline, shows higher toxicity to HAE cells compared to the other cells. Forty-eight-hours incubation of HAE cells with a high concentration of MG (60 µM) provoked apoptotic cell death, which was probably due to signaling through enhanced reactive oxygen species (ROS) generation and resultant caspase activation. Treatment of the cells with MG at sublethal concentrations less than 20 µM significantly lowered transendothelial electrical resistance and elevated paracellular permeability, without affecting the cell viability. In addition, the MG-elicited lowering of the resistance was abolished by a ROS inhibitor N-acetyl-L-cysteine and augmented by H 2 O 2 and 9,10-phenanthrenequinone, which generates ROS through its redox cycle. These results suggest the contribution of ROS generation to the increase in endothelial barrier permeability.

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Antinociception, tolerance and withdrawal symptoms induced by 7-hydroxymitragynine, an alkaloid from the Thai medicinal herb Mitragyna speciosa

Cited by 94 publications

References 14 publications

Suspected Adulteration of Commercial Kratom Products with 7-Hydroxymitragynine

Suspected Adulteration of Commercial Kratom Products with 7-Hydroxymitragynine

Orally Active Opioid μ/δ Dual Agonist MGM-16, a Derivative of the Indole Alkaloid Mitragynine, Exhibits Potent Antiallodynic Effect on Neuropathic Pain in Mice

Enhancement of Endothelial Barrier Permeability by Mitragynine

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