Mitragynine (Kratom)-Withdrawal behaviour and cognitive impairments can be ameliorated by an epigenetic mechanism
© 2024 British Pharmacological Society..
BACKGROUND AND PURPOSE: Kratom is a preparation from Mitragyna speciosa, which is used as a natural drug preparation for many purposes around the world. However, an overdose of Kratom may cause addiction-like problems including aversive withdrawal states resulting in cognitive impairments via unknown mechanisms. Its main psychoactive alkaloid is mitragynine, showing opioid-like properties.
EXPERIMENTAL APPROACH: Here, we analysed the neuropharmacological effects of mitragynine compared with morphine withdrawal in rats and searched for a pharmacological treatment option that may reverse the occurring cognitive deficits that usually aggravate withdrawal.
KEY RESULTS: We found that withdrawal from 14-day mitragynine (1-10 mg·kg-1·day-1) treatment caused dose-dependent behavioural withdrawal signs resembling those of morphine (5 mg·kg-1·day-1) withdrawal. However, mitragynine (5 and 10 mg·kg-1·day-1) withdrawal also induced impairments in a passive avoidance task. Mitragynine withdrawal not only reduced hippocampal field excitatory postsynaptic potential (fEPSP) amplitudes in basal synaptic transmission and long-term potentiation (LTP) but also reduced epigenetic markers, such as histone H3K9 and H4K12 expression. At the same time, it up-regulates HDAC2 expression. Targeting the epigenetic adaptations with the HDAC inhibitor, SAHA, reversed the effects of mitragynine withdrawal on epigenetic dysregulation, hippocampal input/output curves, paired-pulse facilitation, LTP and attenuated the cognitive deficit. However, SAHA amplified the effects of morphine withdrawal.
CONCLUSION AND IMPLICATIONS: The data from this work show that changes in histone expression and downstream hippocampal plasticity may explain mitragynine, but not morphine, withdrawal behaviours and cognitive impairments. Thus, it may provide a new treatment approach for aversive Kratom/mitragynine withdrawal and addiction.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2024 |
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| Enthalten in: |
British journal of pharmacology - (2024) vom: 25. März |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Yunusa, Suleiman [VerfasserIn] |
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| Links: |
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| Themen: |
Cognitive deficits |
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| Anmerkungen: |
Date Revised 25.03.2024 published: Print-Electronic Citation Status Publisher |
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| doi: |
10.1111/bph.16352 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM370130448 |
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| 520 | |a © 2024 British Pharmacological Society. | ||
| 520 | |a BACKGROUND AND PURPOSE: Kratom is a preparation from Mitragyna speciosa, which is used as a natural drug preparation for many purposes around the world. However, an overdose of Kratom may cause addiction-like problems including aversive withdrawal states resulting in cognitive impairments via unknown mechanisms. Its main psychoactive alkaloid is mitragynine, showing opioid-like properties | ||
| 520 | |a EXPERIMENTAL APPROACH: Here, we analysed the neuropharmacological effects of mitragynine compared with morphine withdrawal in rats and searched for a pharmacological treatment option that may reverse the occurring cognitive deficits that usually aggravate withdrawal | ||
| 520 | |a KEY RESULTS: We found that withdrawal from 14-day mitragynine (1-10 mg·kg-1·day-1) treatment caused dose-dependent behavioural withdrawal signs resembling those of morphine (5 mg·kg-1·day-1) withdrawal. However, mitragynine (5 and 10 mg·kg-1·day-1) withdrawal also induced impairments in a passive avoidance task. Mitragynine withdrawal not only reduced hippocampal field excitatory postsynaptic potential (fEPSP) amplitudes in basal synaptic transmission and long-term potentiation (LTP) but also reduced epigenetic markers, such as histone H3K9 and H4K12 expression. At the same time, it up-regulates HDAC2 expression. Targeting the epigenetic adaptations with the HDAC inhibitor, SAHA, reversed the effects of mitragynine withdrawal on epigenetic dysregulation, hippocampal input/output curves, paired-pulse facilitation, LTP and attenuated the cognitive deficit. However, SAHA amplified the effects of morphine withdrawal | ||
| 520 | |a CONCLUSION AND IMPLICATIONS: The data from this work show that changes in histone expression and downstream hippocampal plasticity may explain mitragynine, but not morphine, withdrawal behaviours and cognitive impairments. Thus, it may provide a new treatment approach for aversive Kratom/mitragynine withdrawal and addiction | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Kratom | |
| 650 | 4 | |a LTP | |
| 650 | 4 | |a SAHA | |
| 650 | 4 | |a cognitive deficits | |
| 650 | 4 | |a histones | |
| 650 | 4 | |a mitragynine | |
| 650 | 4 | |a morphine withdrawal | |
| 700 | 1 | |a Müller, Christian P |e verfasserin |4 aut | |
| 700 | 1 | |a Hassan, Zurina |e verfasserin |4 aut | |
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