Abstract
Chronic administration of opioids produces physical dependence and opioid-induced hyperalgesia. Users claim the Thai traditional tea “kratom” and component alkaloid mitragynine ameliorate opioid withdrawal without increased sensitivity to pain. Testing these claims, we assessed the combined kratom alkaloid extract (KAE) and two individual alkaloids, mitragynine (MG) and the analog mitragynine pseudoindoxyl (MP), evaluating their ability to produce physical dependence and induce hyperalgesia after chronic administration, and as treatments for withdrawal in morphine-dependent subjects. C57BL/6J mice (n = 10/drug) were administered repeated saline, or graded, escalating doses of morphine (intraperitoneal; i.p.), kratom alkaloid extract (orally, p.o.), mitragynine (p.o.), or MP (subcutaneously, s.c.) for 5 days. Mice treated chronically with morphine, KAE, or mitragynine demonstrated significant drug-induced hyperalgesia by day 5 in a 48 °C warm-water tail-withdrawal test. Mice were then administered naloxone (10 mg/kg, s.c.) and tested for opioid withdrawal signs. Kratom alkaloid extract and the two individual alkaloids demonstrated significantly fewer naloxone-precipitated withdrawal signs than morphine-treated mice. Additional C57BL/6J mice made physically dependent on morphine were then used to test the therapeutic potential of combined KAE, mitragynine, or MP given twice daily over the next 3 days at either a fixed dose or in graded, tapering descending doses. When administered naloxone, mice treated with KAE, mitragynine, or MP under either regimen demonstrated significantly fewer signs of precipitated withdrawal than control mice that continued to receive morphine. In conclusion, while retaining some liabilities, kratom, mitragynine, and mitragynine pseudoindoxyl produced significantly less physical dependence and ameliorated precipitated withdrawal in morphine-dependent animals, suggesting some clinical value.
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This research was supported by Grants from the National Institute on Drug Abuse RO1DA046487 and R21/R33 DA045884 (to SM), Cancer Center Support Grant P30 CA008748 from the National Cancer Institute (to MSKCC), and funds from the University of Florida (to JPM).
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SM, JPM and LLW participated in research design and wrote and contributed to the writing of manuscript. TJC, SOE, CAS, HMS and LLW conducted experiments. SM, SC and RU contributed new reagents or analytic tools. JPM and LLW performed data analysis. All authors critically reviewed the content and approved the final version for publication.
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All animal studies were preapproved by the University of Florida (Gainesville, FL, USA) Institutional Animal Care and Use Committee, in accordance with the 2011 National Institute of Health Guide for the Care and Use of Laboratory Animals. Animal studies are reported in compliance with the ARRIVE guidelines (Kilkenny et al. 2010). Initial sample sizes were approximated by power analysis, with animals assigned to groups randomly. Drug treatment experiments were conducted in a blinded fashion.
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This manuscript contributes to the Special Issue to honor Professor Gavril W. Pasternak, who passed on Feb 22nd, 2019. The authors dedicate this work to his memory, teachings and friendship.
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Wilson, L.L., Chakraborty, S., Eans, S.O. et al. Kratom Alkaloids, Natural and Semi-Synthetic, Show Less Physical Dependence and Ameliorate Opioid Withdrawal. Cell Mol Neurobiol 41, 1131–1143 (2021). https://doi.org/10.1007/s10571-020-01034-7
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DOI: https://doi.org/10.1007/s10571-020-01034-7