Acute mitragynine administration suppresses cortical oscillatory power and systems theta coherence in rats

Abstract

<jats:sec><jats:title>Background:</jats:title><jats:p> Mitragynine is the major alkaloid of Mitragyna speciosa (kratom) with potential as a therapeutic in pain management and in depression. There has been debate over the potential side effects of the drug including addiction risk and cognitive decline. </jats:p></jats:sec><jats:sec><jats:title>Aims:</jats:title><jats:p> To evaluate the effects of mitragynine on neurophysiological systems function in the prefrontal cortex (PFC), cingulate cortex (Cg), orbitofrontal cortex, nucleus accumbens (NAc), hippocampus (HIP), thalamus (THAL), basolateral amygdala (BLA) and ventral tegmental area of rats. </jats:p></jats:sec><jats:sec><jats:title>Methods:</jats:title><jats:p> Local field potential recordings were taken from animals at baseline and for 45 min following mitragynine administration (10 mg/kg, intraperitoneally). Drug-induced changes in spectral power and coherence between regions at specific frequencies were evaluated. Mitragynine-induced changes in c-fos expression were also analyzed. </jats:p></jats:sec><jats:sec><jats:title>Results:</jats:title><jats:p> Mitragynine increased delta power and reduced theta power in all three cortical regions that were accompanied by increased c-fos expression. A transient suppression of gamma power in PFC and Cg was also evident. There were no effects of mitragynine on spectral power in any of the other regions. Mitragynine induced a widespread reduction in theta coherence (7–9 Hz) that involved disruptions in cortical and NAc connectivity with the BLA, HIP and THAL. </jats:p></jats:sec><jats:sec><jats:title>Conclusions:</jats:title><jats:p> These findings show that mitragynine induces frequency-specific changes in cortical neural oscillatory activity that could potentially impact cognitive functioning. However, the absence of drug effects within regions of the mesolimbic pathway may suggest either a lack of addiction potential, or an underlying mechanism of addiction that is distinct from other opioid analgesic agents. </jats:p></jats:sec>

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

“…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).…”

“…Specifically, whereas the extract from Cheaha et al (2015) was enriched with mitragynine, the extract used herein showed significant levels of other alkaloids, two of which that were in greater abundance than mitragynine. Indeed, we have previously shown that synthetic mitragynine has no effects on NAc oscillations ( Thériault et al, 2020 ). Differences in the composition of the extract are also exemplified by the dose used, with their dose as much as 160 times higher than the one used in the present study.…”

“…It is therefore intriguing that although there is some evidence for analgesic and antidepressant properties of kratom alkaloids ( Matsumoto et al, 2004 ; Takayama, 2004 ; Kumarnsit et al, 2007a ; Kumarnsit et al, 2007b ; Sabetghadam et al, 2010 ; Idayu et al, 2011 ; Grundmann, 2017 ), the impact of these alkaloids on the neuronal oscillatory activity in the brain is lacking. Two studies examining the neurophysiological effects of mitragynine in rats did, however, demonstrate frequency-specific changes in cortical oscillatory power ( Yusoff et al, 2016 ; Thériault et al, 2020 ) with no effects in other regions including the VTA, NAc, thalamus, amygdala, or hippocampus ( Thériault et al, 2020 ).…”

A systematic review of (pre)clinical studies on the therapeutic potential and safety profile of kratom in humans

“…This data may be supported by the findings of a recent study that showed LKT to induce fewer side effects (e.g., physical dependence/respiratory depression) compared to MOR without affecting motor activity (Wilson et al., 2020 ). Similarly, some authors reported that mitragynine is a compound with a minor addictive potential (Meepong and Sooksawate, 2019 ; Thériault et al., 2020 ; Yue et al., 2018 ), when compared to MOR (Cheaha et al., 2017 ; Harun et al., 2015 ), neither it caused physiological dependence (Harun et al., 2020 ). Moreover, despite kratom and 7HMG were reported to have rewarding effects (Gutridge et al., 2020 ), with 7HMG having a higher abuse potential (Hassan et al., 2019 ; Sabetghadam et al., 2013 ; Yusoff et al., 2016 ), a recent study found that both mitragynine and 7HMG did not show rewarding actions in the intracranial self‐stimulation (Behnood‐Rod et al., 2020 ).…”

A review on Mitragyna speciosa (Rubiaceae) as a prominent medicinal plant based on ethnobotany, phytochemistry and pharmacological activities

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