UPM Institutional Repository

Mitragynine (Kratom)-induced cognitive impairments in mice resemble Δ9-THC and morphine effects: reversal by cannabinoid CB1 receptor antagonism


Ismail, Nurul Iman and Ahmad, Nur Aimi Zawami and Mohd Yusof, Nurul Aiman and Talib, Ummi Nasrah and Norazit, Anwar and Kumar, Jaya and Mehat, Muhammad Zulfadli and Hassan, Zurina and Muller, Christian P. and Muzaimi, Mustapha (2021) Mitragynine (Kratom)-induced cognitive impairments in mice resemble Δ9-THC and morphine effects: reversal by cannabinoid CB1 receptor antagonism. Frontiers in Pharmacology, 12. art. no. 708055. pp. 1-21. ISSN 1663-9812


Kratom is a widely abused plant-based drug preparation with a global interest in recent years, well beyond its native grounds in Southeast Asia. Mitragynine, its major psychoactive constituent is known to exhibit opioid-like behavioral effects with resultant neuroplasticity in the brain reward system. Its chronic administration is associated with cognitive impairments in animal studies. However, the underlying molecular mechanism for such a deficit remains elusive. In this study, the involvement of cannabinoid type-1 (CB1) receptors in cognitive deficits after chronic mitragynine exposures was investigated for 28 days (with incremental dose sensitization from 1 to 25 mg/kg) in adult male Swiss albino mice using the IntelliCage® system. Chronic high-dose mitragynine exposure (5–25 mg/kg, intraperitoneal [i.p.]), but not low-dose exposure (1–4 mg/kg, i.p.), induced hyperlocomotion, potentiated the preference for sucrose reward, increased resistance to punishment, and impaired place learning and its reversal. Comparable deficits were also observed after chronic treatments with Δ-9-tetrahydrocannabinol (THC, 2 mg/kg, i.p.) or morphine (5 mg/kg, subcutaneous). Mitragynine-, morphine-, and THC-induced learning and memory deficits were reversed by co-treatment with the CB1 receptor antagonist, NIDA-41020 (10 mg/kg, i.p.). A significant upregulation of CB1 receptor expression was found in the hippocampal CA1 region and ventral tegmental area after chronic high-dose mitragynine and morphine, whereas a downregulation was observed after chronic THC. In conclusion, the present study suggests a plausible role of the CB1 receptor in mediating the dose-dependent cognitive deficits after chronic high-dose mitragynine exposure. This also highlights the potential of CB1 receptor antagonism in ameliorating the cognitive deficits associated with long-term kratom/mitragynine consumption in humans.

Download File

Full text not available from this repository.

Additional Metadata

Item Type: Article
Divisions: Faculty of Medicine and Health Science
DOI Number: https://doi.org/10.3389/fphar.2021.708055
Publisher: Frontiers Media
Keywords: Kratom; Mitragynine; Morphine; Δ9-tetrahydrocannabinol (THC); Cannabinoid receptor 1 (CB1); Cognition
Depositing User: Ms. Nur Faseha Mohd Kadim
Date Deposited: 18 May 2023 08:16
Last Modified: 18 May 2023 08:16
Altmetrics: http://www.altmetric.com/details.php?domain=psasir.upm.edu.my&doi=10.3389/fphar.2021.708055
URI: http://psasir.upm.edu.my/id/eprint/94208
Statistic Details: View Download Statistic

Actions (login required)

View Item View Item