Studies Of Mitragynine, The Principle Alkaloid Of Mitragyna Speciosa Korth (Kratom) On Its Abuse And Addictive Properties In Rat Behavioural Models
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Date
2016-03
Authors
Harun, Norsyifa
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Publisher
Universiti Sains Malaysia
Abstract
Mitragynine is the main active alkaloid isolated from the leaves of Mitragyna speciosa or kratom. While mitragynine or kratom provides analgesic, anti-inflammatory and muscle relaxant effects, little is known about its abuse and addictive properties. Given the likely importance of opioid system in mediating the pharmacological effects of mitragynine, the present study aims to explore the behavioural effects of mitragynine using drug discrimination and drug self-administration procedures. Male Sprague Dawley rats were trained to discriminate between mitragynine and vehicle in two-lever drug discrimination procedure under a tandem variable-interval (VI-60 sec) and fixed-ratio (FR-10) schedule of food reinforcement. The rats successfully acquired mitragynine discrimination (15.0 mg/kg, i.p.) which was similar to another group of rats with morphine discrimination (5.0 mg/kg, i.p.). To gain a better understanding on the pharmacological similarities shared between mitragynine and morphine, a similar series of substitution tests were conducted in rats trained to discriminate morphine from vehicle. Mitragynine was fully substituted to the morphine discriminative stimulus and vice versa, suggesting pharmacological similarities between the two drugs. The pharmacological mechanism of mitragynine derivative, 7-hydroxymitragynine with a specific focus on opioid receptor involvement was also examined in rats trained to discriminate morphine from vehicle. The administration of 7-hydroxymitragynine derivative at 3.0 mg/kg (i.p.) dose engendered full substitution to the morphine discriminative stimulus. In order to study the dual actions of mitragynine, the effect of cocaine substitution to the mitragynine discriminative stimulus was performed in mitragynine-trained rats. The mitragynine stimulus was partially substituted to cocaine (10.0 mg/kg, i.p.) stimulus while this effect was not observed in rats trained to discriminate morphine from vehicle. Due to the ‘opioid-like’ subjective properties detected in drug discrimination model, further studies assessed the profile of mitragynine in rat model of fentanyl (i.e. μ-opioid agonist) dependence using two-lever ‘choice’ of self-administration procedure. Mitragynine at three unit doses (0.3, 1.0 and 3.0 mg/kg/infusion) maintained the lever-pressing responses of the fentanyl (2.0 μg/kg/infusion) self-administration. The profile over the mitragynine cross-substitution tests was different from baseline levels observed during extinction tests, suggesting that mitragynine may have its reinforcing effects. Altogether, the discriminative stimulus effect and dependence-producing potential exhibited by mitragynine provide some evidence for its abuse and addictive potential, which may support the classification of mitragynine or kratom as a harmful drug.
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