Tramadol and Codeine Stacking/Boosting Dose Exposure Induced Neurotoxic Behaviors, Oxidative Stress, Mitochondrial Dysfunction, and Neurotoxic Genes in Adolescent Mice.
Codeine-tramadol cocktail
Mitochondrial dysfunction
Neurodegeneration
Neurotoxic genes
Oxidative stress
Stereotypic behavior
Journal
Neurotoxicity research
ISSN: 1476-3524
Titre abrégé: Neurotox Res
Pays: United States
ID NLM: 100929017
Informations de publication
Date de publication:
Oct 2022
Oct 2022
Historique:
received:
10
06
2022
accepted:
28
06
2022
revised:
10
06
2022
pubmed:
14
7
2022
medline:
30
9
2022
entrez:
13
7
2022
Statut:
ppublish
Résumé
In spite of the increasing epidemic of pharmaceutical opioids (codeine and tramadol) misuse and abuse among the adolescents, little is known about the neurotoxic consequences of the widespread practice of tramadol and codeine abuse involving increasing multiple doses across days, referred to as stacking and boosting. Hence, in this study, we replicated stacking and boosting doses of tramadol, codeine alone, or in combination on spontaneous motor activity and cognitive function in adolescent mice and adduced a plausible mechanism of possible neurotoxicity. Ninety-six adolescent mice were randomly distributed into 4 groups (n = 24 per group) and treated thrice daily for 9 days with vehicle, tramadol (20, 40, or 80 mg/kg), codeine (40, 80, or 160 mg/kg), or their combinations. Exposure of mice to tramadol induced hyperactivity and stereotypic behavior while codeine exposure caused hypoactivity and nootropic effect but tramadol-codeine cocktail led to marked reduction in spontaneous motor activity and cognitive function. In addition, tramadol, codeine, and their cocktail caused marked induction of nitroso-oxidative stress and inhibition of mitochondrial complex I activity in the prefrontal cortex (PFC) and midbrain (MB). Real-time PCR expression profiling of genes encoding neurotoxicity (RT) showed that tramadol exposure upregulate 57 and downregulate 16 neurotoxic genes, codeine upregulate 45 and downregulate 25 neurotoxic genes while tramadol-codeine cocktail upregulate 52 and downregulate 20 neurotoxic genes in the PFC. Findings from this study demonstrate that the exposure of adolescents mice to multiple and increasing doses of tramadol, codeine, or their cocktail lead to spontaneous motor coordination deficits indicative of neurotoxicity through induction of oxidative stress, inhibition of mitochondrial complex I activity and upregulation of neurotoxicity encoding genes in mice.
Identifiants
pubmed: 35829998
doi: 10.1007/s12640-022-00539-x
pii: 10.1007/s12640-022-00539-x
doi:
Substances chimiques
Analgesics, Opioid
0
Nootropic Agents
0
Pharmaceutical Preparations
0
Tramadol
39J1LGJ30J
Codeine
UX6OWY2V7J
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1304-1321Subventions
Organisme : Fogarty International Center of the National Institutes of Health
ID : D43TW010134
Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
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