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Sex and Estrous Cycle Differences in Analgesia and Brain Oxycodone Levels

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Abstract

Sex differences in opioid analgesia occur in rodents and humans, and could be due to differences in drug and metabolite levels. Thus, we investigated the sex and cycle differences in analgesia (nociception) from oxycodone in rats and related these to sex and cycle differences in brain and plasma oxycodone and metabolite levels. Since numerous opioids are CYP2D enzyme substrates and variation in CYP2D alters opioid drug levels and response, we also initiated studies to see if the sex and cycle differences observed might be due to differences in brain CYP2D activity. Across oxycodone doses, females in diestrus had higher analgesia (using tail flick latency) compared to males and females in estrus; we also demonstrated a direct effect of estrous cycle on analgesia within females. Consistent with the analgesia, females in diestrus had highest brain oxycodone levels (assessed using microdialysis) compared to males and females in estrus. Analgesia correlated with brain oxycodone, but not brain oxymorphone or noroxycodone levels, or plasma drug or metabolite levels. Propranolol (a CYP2D mechanism–based inhibitor), versus vehicle pre-treatments, increased brain oxycodone, and decreased brain oxymorphone/oxycodone drug level ratios (an in vivo CYP2D activity phenotype in the brain) in males and females in estrus, but not in females in diestrus. Brain oxymorphone/oxycodone inversely correlated with analgesia. Together, both sex and estrous cycle impact oxycodone analgesia and brain oxycodone levels, likely through regulation of brain CYP2D oxycodone metabolism. As CYP2D6 is expressed in human brain, perhaps similar sex and cycle influences also occur in humans.

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Acknowledgements

We would like to thank Dr. Bin Zhao for his invaluable technical assistance with the LC-MS analyses, Dr. Ahmed El-Sherbeni for assistance with MD calculations, and Fariba Baghai Wadji for her expert support with stereotaxic surgeries and microdialysis animal procedures.

Funding

This work was supported by the R01 grant from the National Institutes of Health (DA043526); Canada Research Chairs program (Dr. Tyndale, the Canada Research Chair in Pharmacogenomics), a Canadian Institutes of Health Research (Foundation Grant FDN-154294); the Centre for Addiction and Mental Health; and the CAMH Foundation.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, University of Toronto, Medical Sciences Building Rm. 4326, 1 King’s College Circle, Toronto, ON, M5S 1A8, Canada

    Nicole Arguelles, Sharon Miksys & Rachel F. Tyndale

  2. Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, Canada

    Sharon Miksys & Rachel F. Tyndale

  3. Department of Psychiatry, University of Toronto, Toronto, ON, Canada

    Rachel F. Tyndale

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  1. Nicole Arguelles
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Contributions

N.A., S.M, and R.F.T designed all the research experiments. N.A. did the stereotaxic surgeries and ran all the experiments. N.A. analyzed the data. N.A and R.F.T wrote the manuscript. All the authors discussed the results and commented on the manuscript.

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Correspondence to Rachel F. Tyndale.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. Experiments were performed in accordance with the NIH guidelines for the care and use of laboratory animals, and with approval of the University of Toronto Animal Care Committee.

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Conflict of Interest

Dr. Rachel F Tyndale has consulted for Quinn Emanuel and Ethismos on topics unrelated to this current work. Nicole Arguelles and Dr. Sharon Miksys have no conflicts to declare.

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Arguelles, N., Miksys, S. & Tyndale, R.F. Sex and Estrous Cycle Differences in Analgesia and Brain Oxycodone Levels. Mol Neurobiol 58, 6540–6551 (2021). https://doi.org/10.1007/s12035-021-02560-1

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