7-Hydroxymitragynine Is an Active Metabolite of Mitragynine and a Key Mediator of Its Analgesic Effects

Andrew C. Kruegel, Rajendra Uprety, Steven G. Grinnell, Cory Langreck, Elizabeth A. Pekarskaya, Valerie Le Rouzic, Michael Ansonoff, Madalee M. Gassaway, John Pintar, Gavril W. Pasternak, Jonathan A. Javitch, Susruta Majumdar, Dalibor Sames

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Mitragyna speciosa, more commonly known as kratom, is a plant native to Southeast Asia, the leaves of which have been used traditionally as a stimulant, analgesic, and treatment for opioid addiction. Recently, growing use of the plant in the United States and concerns that kratom represents an uncontrolled drug with potential abuse liability, have highlighted the need for more careful study of its pharmacological activity. The major active alkaloid found in kratom, mitragynine, has been reported to have opioid agonist and analgesic activity in vitro and in animal models, consistent with the purported effects of kratom leaf in humans. However, preliminary research has provided some evidence that mitragynine and related compounds may act as atypical opioid agonists, inducing therapeutic effects such as analgesia, while limiting the negative side effects typical of classical opioids. Here we report evidence that an active metabolite plays an important role in mediating the analgesic effects of mitragynine. We find that mitragynine is converted in vitro in both mouse and human liver preparations to the much more potent mu-opioid receptor agonist 7-hydroxymitragynine and that this conversion is mediated by cytochrome P450 3A isoforms. Further, we show that 7-hydroxymitragynine is formed from mitragynine in mice and that brain concentrations of this metabolite are sufficient to explain most or all of the opioid-receptor-mediated analgesic activity of mitragynine. At the same time, mitragynine is found in the brains of mice at very high concentrations relative to its opioid receptor binding affinity, suggesting that it does not directly activate opioid receptors. The results presented here provide a metabolism-dependent mechanism for the analgesic effects of mitragynine and clarify the importance of route of administration for determining the activity of this compound. Further, they raise important questions about the interpretation of existing data on mitragynine and highlight critical areas for further research in animals and humans.

Original languageEnglish (US)
Pages (from-to)992-1001
Number of pages10
JournalACS Central Science
Volume5
Issue number6
DOIs
StatePublished - Jun 26 2019

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Metabolites
Analgesics
Brain
Animals
Alkaloids
Metabolism
Liver
Opioid Analgesics
Opioid Receptors
mitragynine
7-hydroxymitragynine
Cytochrome P-450 CYP3A
mu Opioid Receptor
Protein Isoforms
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Chemical Engineering(all)

Cite this

Kruegel, A. C., Uprety, R., Grinnell, S. G., Langreck, C., Pekarskaya, E. A., Le Rouzic, V., ... Sames, D. (2019). 7-Hydroxymitragynine Is an Active Metabolite of Mitragynine and a Key Mediator of Its Analgesic Effects. ACS Central Science, 5(6), 992-1001. https://doi.org/10.1021/acscentsci.9b00141
Kruegel, Andrew C. ; Uprety, Rajendra ; Grinnell, Steven G. ; Langreck, Cory ; Pekarskaya, Elizabeth A. ; Le Rouzic, Valerie ; Ansonoff, Michael ; Gassaway, Madalee M. ; Pintar, John ; Pasternak, Gavril W. ; Javitch, Jonathan A. ; Majumdar, Susruta ; Sames, Dalibor. / 7-Hydroxymitragynine Is an Active Metabolite of Mitragynine and a Key Mediator of Its Analgesic Effects. In: ACS Central Science. 2019 ; Vol. 5, No. 6. pp. 992-1001.
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Kruegel, AC, Uprety, R, Grinnell, SG, Langreck, C, Pekarskaya, EA, Le Rouzic, V, Ansonoff, M, Gassaway, MM, Pintar, J, Pasternak, GW, Javitch, JA, Majumdar, S & Sames, D 2019, '7-Hydroxymitragynine Is an Active Metabolite of Mitragynine and a Key Mediator of Its Analgesic Effects', ACS Central Science, vol. 5, no. 6, pp. 992-1001. https://doi.org/10.1021/acscentsci.9b00141

7-Hydroxymitragynine Is an Active Metabolite of Mitragynine and a Key Mediator of Its Analgesic Effects. / Kruegel, Andrew C.; Uprety, Rajendra; Grinnell, Steven G.; Langreck, Cory; Pekarskaya, Elizabeth A.; Le Rouzic, Valerie; Ansonoff, Michael; Gassaway, Madalee M.; Pintar, John; Pasternak, Gavril W.; Javitch, Jonathan A.; Majumdar, Susruta; Sames, Dalibor.

In: ACS Central Science, Vol. 5, No. 6, 26.06.2019, p. 992-1001.

Research output: Contribution to journalArticle

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AU - Kruegel, Andrew C.

AU - Uprety, Rajendra

AU - Grinnell, Steven G.

AU - Langreck, Cory

AU - Pekarskaya, Elizabeth A.

AU - Le Rouzic, Valerie

AU - Ansonoff, Michael

AU - Gassaway, Madalee M.

AU - Pintar, John

AU - Pasternak, Gavril W.

AU - Javitch, Jonathan A.

AU - Majumdar, Susruta

AU - Sames, Dalibor

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N2 - Mitragyna speciosa, more commonly known as kratom, is a plant native to Southeast Asia, the leaves of which have been used traditionally as a stimulant, analgesic, and treatment for opioid addiction. Recently, growing use of the plant in the United States and concerns that kratom represents an uncontrolled drug with potential abuse liability, have highlighted the need for more careful study of its pharmacological activity. The major active alkaloid found in kratom, mitragynine, has been reported to have opioid agonist and analgesic activity in vitro and in animal models, consistent with the purported effects of kratom leaf in humans. However, preliminary research has provided some evidence that mitragynine and related compounds may act as atypical opioid agonists, inducing therapeutic effects such as analgesia, while limiting the negative side effects typical of classical opioids. Here we report evidence that an active metabolite plays an important role in mediating the analgesic effects of mitragynine. We find that mitragynine is converted in vitro in both mouse and human liver preparations to the much more potent mu-opioid receptor agonist 7-hydroxymitragynine and that this conversion is mediated by cytochrome P450 3A isoforms. Further, we show that 7-hydroxymitragynine is formed from mitragynine in mice and that brain concentrations of this metabolite are sufficient to explain most or all of the opioid-receptor-mediated analgesic activity of mitragynine. At the same time, mitragynine is found in the brains of mice at very high concentrations relative to its opioid receptor binding affinity, suggesting that it does not directly activate opioid receptors. The results presented here provide a metabolism-dependent mechanism for the analgesic effects of mitragynine and clarify the importance of route of administration for determining the activity of this compound. Further, they raise important questions about the interpretation of existing data on mitragynine and highlight critical areas for further research in animals and humans.

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Kruegel AC, Uprety R, Grinnell SG, Langreck C, Pekarskaya EA, Le Rouzic V et al. 7-Hydroxymitragynine Is an Active Metabolite of Mitragynine and a Key Mediator of Its Analgesic Effects. ACS Central Science. 2019 Jun 26;5(6):992-1001. https://doi.org/10.1021/acscentsci.9b00141