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Abuse liability of mitragynine assessed with a self-administration procedure in rats

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Abstract

Rationale

Substantial use of the plant kratom for psychoactive effects has driven interest in its abuse liability. Several place conditioning studies suggest abuse liability of the active ingredient mitragynine, though studies of its self-administration have not been published.

Methods

Binding of mitragynine to rat brain mu, kappa, and delta opioid receptors was compared to that for heroin and morphine. Self-administration of mitragynine, heroin, methamphetamine, or saline was assessed during single-session substitutions in rats trained to self-administer methamphetamine (0.022 mg/kg/injection, i.v.) during 1-h daily sessions.

Results

Mitragynine had > 2- or ~ 16-fold greater affinity for the mu opioid receptor than, respectively, for kappa or delta opioid receptors. Its affinity for the mu receptor was ~ 200-fold less than that for morphine. In rats trained to self-administer methamphetamine, saline substitutions significantly decreased the number of responses, whereas different doses of methamphetamine (0.002–0.068 mg/kg/injection) or heroin (0.001–0.03 mg/kg/injection) maintained self-administration with maximal responding at 0.022 or 0.01 mg/kg/injection, respectively. In contrast, no dose of mitragynine maintained response rates greater than those obtained with saline. Presession mitragynine treatment (0.1 to 3.0 mg/kg) decreased response rates maintained by heroin but had little effect on responding maintained by methamphetamine across the same range of doses.

Conclusions

These results suggest a limited abuse liability of mitragynine and potential for mitragynine treatment to specifically reduce opioid abuse. With the current prevalence of opioid abuse and misuse, it appears currently that mitragynine is deserving of more extensive exploration for its development or that of an analog as a medical treatment for opioid abuse.

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Acknowledgments

We thank Drs. Christopher R. McCurdy for the initial advice on mitragynine and James H. Woods for the advice on the writing of this report.

Funding

This project was funded by the National Natural Science Foundation of China (81302762) and the National Institute on Drug Abuse, Intramural Research Program. These studies were initiated at NIDA when Kai Yue was funded by a scholarship from the China Scholarship Council (CSC), a non-profit institution affiliated with the Ministry of Education of the P.R. China, Level 13, Building A3, No. 9 Chegongzhuang Avenue, Beijing 100044, P. R. China.

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Authors and Affiliations

  1. Wuhan Institute of Biomedical Science, Jianghan University, No. 8 Sanjiaohu Street, Wuhan, China

    Kai Yue

  2. Psychobiology Section, Molecular Neuropsychiatry Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, 251 Bayview Blvd., Baltimore, MD, 21224, USA

    Theresa A. Kopajtic & Jonathan L. Katz

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  1. Kai Yue
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  2. Theresa A. Kopajtic
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  3. Jonathan L. Katz
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Correspondence to Jonathan L. Katz.

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Yue, K., Kopajtic, T.A. & Katz, J.L. Abuse liability of mitragynine assessed with a self-administration procedure in rats. Psychopharmacology 235, 2823–2829 (2018). https://doi.org/10.1007/s00213-018-4974-9

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  • DOI: https://doi.org/10.1007/s00213-018-4974-9

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