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Assessing physiological dependence and withdrawal potential of mitragynine using schedule-controlled behaviour in rats

Lookup NU author(s): Dr Mohammed Shoaib



This is the authors' accepted manuscript of an article that has been published in its final definitive form by Springer, 2020.

For re-use rights please refer to the publisher's terms and conditions.


Rationale Kratom is proposed to exhibit therapeutic potential as an opium substitute, but little is known about its dependenceproducing profile, particularly of its main psychoactive compound, mitragynine (MG). Objectives This study examined the dependence-producing effects of MG using operant-scheduled behaviour in rats and investigated the potential therapeutic effect of MG by comparing effects to buprenorphine in morphine-dependent rats using the same schedule-controlled behavioural task. Methods The effects of acutely administered MG and morphine were determined in rats trained to respond under fixed-ratio (FR) 10 schedule of food reinforcement. Next, the rats were administered MG and morphine twice daily for 14 consecutive days to determine if physiological dependence would develop by examining cessation of drug treatment and following antagonistprecipitated withdrawal. The study then examined the effects of MG substitution to suppress naloxone-precipitated morphine withdrawal effects on scheduled responding. Results Acute doses of MG did not produce dose-related decreases on FR schedules of responding compared to morphine. Unlike morphine, MG-treated rats showed no suppression of response rates following cessation of MG treatment. However, withdrawal effects were evident for MG after precipitation by either naloxone or SR141716A (rimonabant), similar to morphinetreated rats. MG in higher doses (10 and 30 mg/kg) attenuated the naloxone-precipitated morphine withdrawal effects while smaller doses of buprenorphine (0.3 and 1.0 mg/kg) were necessary to alleviate these effects. Conclusion The findings suggest that MG does not induce physiological dependence but can alleviate the physical symptoms associated with morphine withdrawal which represent the desired characteristics of novel pharmacotherapeutic interventions for managing opioid use disorder (OUD)

Publication metadata

Author(s): Harun H, Johari IS, Mansor SM, Shoaib M

Publication type: Article

Publication status: Published

Journal: Psychopharmacology

Year: 2020

Volume: 237

Pages: 855-867

Online publication date: 12/12/2019

Acceptance date: 27/11/2019

Date deposited: 24/02/2020

ISSN (print): 0033-3158

ISSN (electronic): 1432-2072

Publisher: Springer


DOI: 10.1007/s00213-019-05418-6


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