Cross-reinstatement of mitragynine and morphine place preference in rats

Japarin, Rima Atria; Yusoff, Nurul H.M.; Hassan, Zurina; Müller, Christian P.; Harun, Norsyifa

doi:10.1016/j.bbr.2020.113021

Cited by 13 publications

(13 citation statements)

References 72 publications

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“…The fact that neither model showed any reinstatement effect at a lower MG priming dose (3 mg/kg) further suggested that the reinstatement of morphine-seeking behaviour by MG exposure in this study was dose-dependent. In contrast to the CPP study, where MG at a 30 mg/kg dose reinstated the morphine-induced CPP as observed by a significantly greater amount of time spent in the drug-paired compartment (Japarin et al, 2021), MG priming at this dose resulted in a relatively low level of morphine-lever responding in the present study. This could be explained by the fact that MG at this relatively high dose may nonspecifically suppress response rates.…”

Section: Discussioncontrasting

confidence: 99%

“…According to preclinical studies, the most plausible mechanism behind the neuropharmacological basis of kratom use by opioid users is its interaction with the opioid system (Harun et al, 2015(Harun et al, , 2022Japarin et al, 2021). The pharmacological effects of kratom are believed to be attributed to its alkaloids, especially the main active constituent, mitragynine (MG), which makes up about 66% of the total amount of alkaloids present in the kratom plant extract (Ponglux et al, 1994;Hassan et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

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Mitragynine, a primary constituent of kratom reinstates morphine-seeking behaviour in rats

Japarin

Harun

Hassan

et al. 2022

Behavioural Pharmacology

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Mitragynine (MG) is a pharmacologically active alkaloid derived from the leaves of Mitragyna speciosa Korth (Kratom). This plant has sparked significant interest as a potential alternative treatment for managing opioid dependence and withdrawal due to its opioid-like pharmacological effects. However, whether MG exposure would trigger opioid-seeking behaviour following abstinence has not been investigated. The present study examined the effects of MG priming on morphineseeking behaviour in rats. Male Sprague-Dawley rats were initially trained to intravenously self-administer morphine (0.5 mg/kg/infusion) under a fixed ratio-3 schedule of reinforcement. Removal of both morphine infusions and drug-associated cues led to the subsequent extinction of the drug-seeking behaviour. Tests of reinstatement were made following exposure to a randomised order of intraperitoneal injections of MG (3, 10 and 30 mg/ kg), morphine (5 mg/kg) and vehicle. Significant levels of drug-seeking behaviour were observed following extended access to morphine self-administration, which was extinguished following removal of morphine and cues indicative of morphine-seeking behaviour, supporting the relapse model. The present finding demonstrated that MG priming in a dose of 10 mg/kg resulted in the reinstatement of morphine-seeking behaviour, whereas the higher MG dose (30 mg/kg) tested suppressed the seeking response. This study indicated that exposure to a low MG dose may increase the likelihood of relapsing to opioids, suggesting that the potential of MG as a treatment for opioid management merits further scientific assessment of its ability to trigger relapse to opioid abuse.

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Section: Discussioncontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mitragynine, a primary constituent of kratom reinstates morphine-seeking behaviour in rats

Japarin

Harun

Hassan

et al. 2022

Behavioural Pharmacology

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“…At the doses employed in the present study, animals showed no adverse effects with acute or repeated administration. We have previously characterized isolated mitragynine effects (10 mg/kg i.p., a standard dose used in the literature (Foss et al, 2020;Japarin et al, 2021;Suhaimi et al, 2021)) on neuronal oscillatory activity where we showed moderate frequency-specific changes in cortical regions only (Thériault et al, 2020). Further, our preliminary behavioural findings showed no effects of the same 10 mg/kg dose of mitragynine on behavioural responses in the tail-flick test (Supplementary Figure S1).…”

Section: Drugssupporting

confidence: 53%

The Antidepressant-Like and Analgesic Effects of Kratom Alkaloids are accompanied by Changes in Low Frequency Oscillations but not ΔFosB Accumulation

et al. 2021

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Mitragyna speciosa (“kratom”), employed as a traditional medicine to improve mood and relieve pain, has shown increased use in Europe and North America. Here, the dose-dependent effects of a purified alkaloid kratom extract on neuronal oscillatory systems function, analgesia, and antidepressant-like behaviour were evaluated and kratom-induced changes in ΔFosB expression determined. Male rats were administered a low or high dose of kratom (containing 0.5 or 1 mg/kg of mitragynine, respectively) for seven days. Acute or repeated low dose kratom suppressed ventral tegmental area (VTA) theta oscillatory power whereas acute or repeated high dose kratom increased delta power, and reduced theta power, in the nucleus accumbens (NAc), prefrontal cortex (PFC), cingulate cortex (Cg) and VTA. The repeated administration of low dose kratom additionally elevated delta power in PFC, decreased theta power in NAc and PFC, and suppressed beta and low gamma power in Cg. Suppressed high gamma power in NAc and PFC was seen selectively following repeated high dose kratom. Both doses of kratom elevated NAc-PFC, VTA-NAc, and VTA-Cg coherence. Low dose kratom had antidepressant-like properties whereas both doses produced analgesia. No kratom-induced changes in ΔFosB expression were evident. These results support a role for kratom as having both antidepressant and analgesic properties that are accompanied by specific changes in neuronal circuit function. However, the absence of drug-induced changes in ΔFosB expression suggest that the drug may circumvent this cellular signaling pathway, a pathway known for its significant role in addiction.

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“…Various MG preparations produced mixed CPP effects with some suggesting abuse potential at high doses. A low priming injection of MG or morphine reinstated CPP after establishment with either drug, suggesting rewarding effects for both (Japarin et al, 2021). Baclofen pretreatment prevented the acquisition and expression of MG-induced CPP (Yusoff et al, 2018).…”

Section: Conditioned Place Preferencementioning

confidence: 90%

“…Factor 1: Actual or relative potential for abuse Intravenous Self-Administration (IV SA) (Prozialeck et al, 2019), (Grundmann et al, 2018;Yue et al, 2018;Coe et al, 2019;Hemby et al, 2019;Garcia-Romeu et al, 2020) No evidence of reward MG pretreatment reduced morphine self-administration Intracranial Self-Stimulation (ICSS) (Negus andMiller, 2014)-(Behnood-Rod et al, 2020) No evidence of reward for MG or 7-OH-MG Drug Discrimination (Hiranita et al, 2020;Reeve et al, 2020;Obeng et al, 2021) MG showed partial generalization to multiple drugs, including morphine Strongest generalization of MG was to unscheduled drugs: phenylephrine and lofexidine 7-OH-MG showed full generalization to morphine Conditioned Place Preference (CPP) (Yusoff et al, 2018;Vijeepallam et al, 2019;Wilson et al, 2020;Japarin et al, 2021) Mixed evidence of CPP Physical Dependence/ Withdrawal (Harun et al, 2020;Hassan et al, 2020;Johari et al, 2021;Hassan et al, 20211778;Harun et al, 2021a) Mixed evidence of weak withdrawal across studies relative to morphine MG reduces morphine withdrawal and differs from morphine withdrawal on some measures Survey Data (Prozialeck et al, 2019), (Grundmann et al, 2018;Coe et al, 2019;Garcia-Romeu et al, 2020), (Singh et al, 2014;Galbis-Reig, 2016;Swogger and Walsh, 2018;Smith et al, 2019; (Prozialeck et al, 2019), (Behnood-Rod et al, 2020), (Hassan et al, 2019;Hiranita et al, 2019;Kruegel et al, 2019;…”

Section: Factor/description Citations Main Findings Commentsmentioning

confidence: 99%

Kratom Abuse Potential 2021: An Updated Eight Factor Analysis

Henningfield¹,

Wang²,

Huestis³

2022

Front. Pharmacol.

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Drugs are regulated in the United States (US) by the Controlled Substances Act (CSA) if assessment of their abuse potential, including public health risks, show such control is warranted. An evaluation via the 8 factors of the CSA provides the comprehensive assessment required for permanent listing of new chemical entities and previously uncontrolled substances. Such an assessment was published for two kratom alkaloids in 2018 that the Food and Drug Administration (FDA) have identified as candidates for CSA listing: mitragynine (MG) and 7-hydroxymitragynine (7-OH-MG) (Henningfield et al., 2018a). That assessment concluded the abuse potential of MG was within the range of many other uncontrolled substances, that there was not evidence of an imminent risk to public health, and that a Schedule I listing (the only option for substances that are not FDA approved for therapeutic use such as kratom) carried public health risks including drug overdoses by people using kratom to abstain from opioids. The purpose of this review is to provide an updated abuse potential assessment reviewing greater than 100 studies published since January 1, 2018. These include studies of abuse potential and physical dependence/withdrawal in animals; in-vitro receptor binding; assessments of potential efficacy treating pain and substance use disorders; pharmacokinetic/pharmacodynamic studies with safety-related findings; clinical studies of long-term users with various physiological endpoints; and surveys of patterns and reasons for use and associated effects including dependence and withdrawal. Findings from these studies suggest that public health is better served by assuring continued access to kratom products by consumers and researchers. Currently, Kratom alkaloids and derivatives are in development as safer and/or more effective medicines for treating pain, substances use disorders, and mood disorders. Placing kratom in the CSA via scheduling would criminalize consumers and possession, seriously impede research, and can be predicted to have serious adverse public health consequences, including potentially thousands of drug overdose deaths. Therefore, CSA listing is not recommended. Regulation to minimize risks of contaminated, adulterated, and inappropriately marketed products is recommended.

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Cross-reinstatement of mitragynine and morphine place preference in rats

Cited by 13 publications

References 72 publications

Mitragynine, a primary constituent of kratom reinstates morphine-seeking behaviour in rats

Mitragynine, a primary constituent of kratom reinstates morphine-seeking behaviour in rats

The Antidepressant-Like and Analgesic Effects of Kratom Alkaloids are accompanied by Changes in Low Frequency Oscillations but not ΔFosB Accumulation

Kratom Abuse Potential 2021: An Updated Eight Factor Analysis

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