Discriminative stimulus properties of mitragynine (kratom) in rats
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Mitragynine (MG) is the primary active alkaloid extracted from the leaves of Mitragyna speciosa or kratom and exhibits pharmacological activities mediated by opioid receptors. The plant has been traditionally used for its opium and psychostimulant-like effects to increase work efficiency or as a substitute in the self-treatment of opiate addiction.
The present study was performed to investigate the discriminative stimulus effects of MG in rats. The pharmacological mechanism of MG action and its derivative, 7-hydroxymitragynine (7-HMG) with a specific focus on opioid receptor involvement was examined in rats trained to discriminate morphine from vehicle. In order to study the dual actions of MG, the effect of cocaine substitution to the MG discriminative stimulus was also performed in MG-trained rats.
Male Sprague Dawley rats were trained to discriminate MG from vehicle in a two-lever drug discrimination procedure under a tandem variable-interval (VI 60’) fixed-ratio (FR 10) schedule of food reinforcement.
Rats acquired the MG discrimination (15.0 mg/kg, i.p.) which was similar to the acquisition of morphine discrimination (5.0 mg/kg, i.p.) in another group of rats. MG substituted fully to the morphine discriminative stimulus in a dose-dependent manner, suggesting pharmacological similarities between the two drugs. The administration of 7-HMG derivative in 3.0 mg/kg (i.p.) dose engendered full generalisation to the morphine discriminative stimulus. In addition, the MG stimulus also partially generalised to cocaine (10.0 mg/kg, i.p.) stimulus.
The present study demonstrates that the discriminative stimulus effect of MG possesses both opioid- and psychostimulant-like subjective effects.
KeywordsMitragynine Kratom Drug discrimination Morphine Opioid Cocaine Rats
This research received financial support from Higher Education Centre of Excellence (HiCoE) special funding (304/CDADAH/650527/K134), USM Research University Grant (RUT) [1001/CDADAH/855005], International Research Collaboration Fund (1002/CDADAH/910410) and MyBrain15 Scholarship from Ministry of Higher Education.
Conflict of interest
- Burkill IH (1935) A dictionary of the Economic Products of the Malay Peninsula. II: 1480-1483Google Scholar
- Grewal KS (1932a) Observations on the pharmacology of mitragynine. J Pharmacol Exp Ther 46:251–271Google Scholar
- Hassan Z, Muzaimi M, Navaratnam V, Yusoff NH, Suhaimi FW, Vadivelu R, Vicknasingam BK, Amato D, von Horsten S, Ismail NI, Jayabalan N, Hazim AI, Mansor SM, Muller CP (2013) From Kratom to mitragynine and its derivatives: physiological and behavioural effects related to use, abuse, and addiction. Neurosci Biobehav Rev 37:138–151PubMedCrossRefGoogle Scholar
- Janchawee B, Keawpradub N, Chittrakarn S, Prasettho S, Wararatananurak P, Sawangjareon K (2007) A high-performance liquid chromatographic method for determination of mitragynine in serum and its application to a pharmacokinetic study in rats. Biomed Chromatogr: BMC 21:176–183PubMedCrossRefGoogle Scholar
- Macko E, Weisbach JA, Douglas B (1972) Some observations on the pharmacology of mitragynine. Arch Int de Pharmacodynamieet de Therapie 198:145–161Google Scholar
- Matsumoto K, Hatori Y, Murayama T, Tashima K, Wongseripipatana S, Misawa K, Kitajima M, Takayama H, Horie S (2006) Involvement of mu-opioid receptors in antinociception and inhibition of gastrointestinal transit induced by 7-hydroxymitragynine, isolated from Thai herbal medicine Mitragyna speciosa. Eur J Pharmacol 549:63–70PubMedCrossRefGoogle Scholar
- Norakanphadung P (1966) Pramuan Khuamru Ruang Yaseptit Hai Thot. Thanyarak Hospital, BangkokGoogle Scholar
- Overton DA (1988) Similarities and differences between behavioural control by drug-produced stimuli and by sensory stimuli. Psychopharmacology 4:176–198Google Scholar
- Reanmongkol W, Keaupradub N, Sawangjaroen K (2007) Effects of the extracts from Mitragyna speciosa korth. Leaves on analgesic and behavioral activities in experimental animals. J Sci Technol 29:39–48Google Scholar
- Sabetghadam A, Ramanathan S, Mansor SM (2010) The evaluation of antinociceptive activity of alkaloid, methanolic, and aqueous extracts of Malaysian Mitragyna speciosa Korth leaves in rats. Pharmacogn Res 2:181–185Google Scholar
- Takayama H, Ishikawa H, Kurihara M, Kitajima M, Aimi N, Ponglux D, Koyama F, Matsumoto K, Moriyama T, Yamamoto LT, Watanabe K, Murayama T, Horie S (2002) Studies on the synthesis and opioid agonistic activities of mitragynine-related indole alkaloids: discovery of opioid agonists structurally different from other opioid ligands. J Med Chem 45:1949–1956PubMedCrossRefGoogle Scholar
- Taufik Hidayat M, Apryani E, Nabishah BM, Moklas MAA, Sharida F, Farhan MA (2010) Determination of mitragynine bound opioid receptors. Adv in Med Dent Sci 3:65–70Google Scholar
- Watanabe K, Yano S, Horie S, Yamamoto LT (1997) Inhibitory effect of mitragynine, an alkaloid with analgesic effect from Thai medicinal plant Mitragyna speciosa, on electrically stimulated contraction of isolated guinea-pig ileum through the opioid receptor. Life Sci 60:933–942PubMedCrossRefGoogle Scholar
- Wray L (1907) “Biak”: an opium substitute. J Fed Malay States Mus 2:53–54Google Scholar
- Yamamoto LT, Horie S, Takayama H, Aimi N, Sakai S, Yano S, Shan J, Pang PK, Ponglux D, Watanabe K (1999) Opioid receptor agonistic characteristics of mitragynine pseudoindoxyl in comparison with mitragynine derived from Thai medicinal plant Mitragyna speciosa. Gen Pharmacol 33:73–78PubMedCrossRefGoogle Scholar