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Tramadol and Codeine Stacking/Boosting Dose Exposure Induced Neurotoxic Behaviors, Oxidative Stress, Mitochondrial Dysfunction, and Neurotoxic Genes in Adolescent Mice

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Abstract

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.

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Acknowledgements

Research reported in this publication was supported by the Fogarty International Center of the National Institutes of Health under Award Number D43TW010134. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Authors and Affiliations

  1. Department of Pharmacology, Therapeutics and Toxicology, Faculty of Basic Medical Sciences, College of Medicine, University of Lagos, Lagos State, Nigeria

    I. O. Ishola, S. U. Eneanya & A. J. Abosi

  2. Department of Veterinary Anatomy, University of Ibadan, Ibadan Oyo State, Nigeria

    O. R. Folarin & J. O. Olopade

  3. Neuroimmunology Group, Molecular Drug Metabolism and Toxicology Laboratory, Department of Biochemistry, University of Ibadan, Ibadan, Nigeria

    I. O. Awogbindin

  4. Department of Medicine, Neurology Unit, College of Medicine, University of Lagos, Lagos State, Nigeria

    N. U. Okubadejo

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  1. I. O. Ishola
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  2. S. U. Eneanya
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  3. O. R. Folarin
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  4. I. O. Awogbindin
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  6. J. O. Olopade
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Contributions

IOI and NUO conceived and designed this study. IOI, SUE, AJA, IOA, and ORF conducted the experiments and data analysis, IOI, SUE, JOO, IOA, and NUO interpreted the data and wrote the manuscript.

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Correspondence to I. O. Ishola.

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Ishola, I.O., Eneanya, S.U., Folarin, O.R. et al. Tramadol and Codeine Stacking/Boosting Dose Exposure Induced Neurotoxic Behaviors, Oxidative Stress, Mitochondrial Dysfunction, and Neurotoxic Genes in Adolescent Mice. Neurotox Res 40, 1304–1321 (2022). https://doi.org/10.1007/s12640-022-00539-x

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