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Oxycodone-Mediated Activation of the Mu Opioid Receptor Reduces Whole Brain Functional Connectivity in Mice

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    Oxycodone-Mediated Activation of the Mu Opioid Receptor Reduces Whole Brain Functional Connectivity in Mice
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    • Md Taufiq Nasseef
      Md Taufiq Nasseef
      Douglas Hospital Research Center, Department of Psychiatry, School of Medicine, McGill University, Montreal, Quebec H4H 1R3, Canada
      More by Md Taufiq Nasseef
    • Jai Puneet Singh
      Jai Puneet Singh
      Douglas Hospital Research Center, Department of Psychiatry, School of Medicine, McGill University, Montreal, Quebec H4H 1R3, Canada
      More by Jai Puneet Singh
    • Aliza T. Ehrlich
      Aliza T. Ehrlich
      Douglas Hospital Research Center, Department of Psychiatry, School of Medicine, McGill University, Montreal, Quebec H4H 1R3, Canada
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    • Michael McNicholas
      Michael McNicholas
      Douglas Hospital Research Center, Department of Psychiatry, School of Medicine, McGill University, Montreal, Quebec H4H 1R3, Canada
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    • Da Woon Park
      Da Woon Park
      Douglas Hospital Research Center, Department of Psychiatry, School of Medicine, McGill University, Montreal, Quebec H4H 1R3, Canada
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    • Weiya Ma
      Weiya Ma
      Douglas Hospital Research Center, Department of Psychiatry, School of Medicine, McGill University, Montreal, Quebec H4H 1R3, Canada
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    • Praveen Kulkarni
      Praveen Kulkarni
      Center for Translational Neuro-Imaging, Northeastern University, Boston, Massachusetts 02115, United States
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    • Brigitte L. Kieffer*
      Brigitte L. Kieffer
      Douglas Hospital Research Center, Department of Psychiatry, School of Medicine, McGill University, Montreal, Quebec H4H 1R3, Canada
      *Tel.: 514 761-6131 ext: 3175. Fax: 514 762-3033. E-mail: [email protected]
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    • Emmanuel Darcq*
      Emmanuel Darcq
      Douglas Hospital Research Center, Department of Psychiatry, School of Medicine, McGill University, Montreal, Quebec H4H 1R3, Canada
      *Tel.: 514 761-6131 ext: 4772. E-mail: [email protected]
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      Orcidhttp://orcid.org/0000-0002-8377-8015
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    ACS Pharmacology & Translational Science

    Cite this: ACS Pharmacol. Transl. Sci. 2019, 2, 4, 264–274
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acsptsci.9b00021
    Published June 28, 2019
    Copyright © 2019 American Chemical Society
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    Abstract

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    Oxycodone is a potent medicinal opioid analgesic to treat pain. It is also addictive and a main cause for the current opioid crisis. At present, the impact of oxycodone on coordinated brain network activities, and contribution of the mu opioid receptor (MOR) to these effects, is unknown. We used pharmacological magnetic resonance imaging in mice to characterize MOR-mediated oxycodone effects on whole-brain functional connectivity (FC). Control (CTL) and MOR knockout (KO) animals were imaged under dexmedetomidine in a 7Tesla scanner. Acquisition was performed continuously before and after 2 mg/kg oxycodone administration (analgesic in CTL mice). Independent component analysis (data-driven) produced a correlation matrix, showing widespread oxycodone-induced reduction of FC across 71 components. Isocortex, nucleus accumbens (NAc), pontine reticular nucleus, and periacqueducal gray (PAG) components showed the highest number of significant changes. Seed-to-voxel FC analysis (hypothesis-driven) was then focused on PAG and NAc considered key pain and reward centers. The two seeds showed reduced FC with 8 and 22 Allen Brain Atlas-based regions, respectively, in CTL but not KO mice. Further seed-to-seed quantification showed highest FC modifications of both PAG and NAc seeds with hypothalamic and amygdalar areas, as well as between them, revealing the strongest impact across reward and aversion/pain centers of the brain. In conclusion, we demonstrate that oxycodone reduces brain communication in a MOR-dependent manner, and establish a preliminary whole-brain FC signature of oxycodone. This proof-of-principle study provides a unique platform and reference data set to test other MOR opioid agonists and perhaps discover new mechanisms and FC biomarkers predicting safer analgesics.

    Copyright © 2019 American Chemical Society

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    Supporting Information

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsptsci.9b00021.

    • Number of FC alterations induced by oxycodone for each component in CTL animals; quantification of oxycodone-induced reduction of FC between voxels from the PAG seed and voxels from 8 other seeds; quantification of oxycodone-induced reduction of FC between voxels from the NAc seed and voxels from 22 other seeds; additional figures (PDF)

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    Cited By

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    This article is cited by 14 publications.

    1. Arakawa Hiroyuki, Ozawa Akihiko. Serotonin circuits act cooperatively with pathophysiology of opioid use disorder. Addiction Neuroscience 2025, 14 , 100187. https://doi.org/10.1016/j.addicn.2024.100187
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    3. Marion Sourty, Cédric Champagnol-Di Liberti, Md Taufiq Nasseef, Lola Welsch, Vincent Noblet, Emmanuel Darcq, Brigitte L. Kieffer. Chronic Morphine Leaves a Durable Fingerprint on Whole-Brain Functional Connectivity. Biological Psychiatry 2024, 96 (9) , 708-716. https://doi.org/10.1016/j.biopsych.2023.12.007
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    6. Helen M. Kamens, Samuel Cramer, Rachel N. Hanley, Spencer Chase, Anna Wickenheisser, William J. Horton, Nanyin Zhang. Neuroimaging of opioid exposure: a review of preclinical animal models to inform addiction research. Psychopharmacology 2023, 240 (12) , 2459-2482. https://doi.org/10.1007/s00213-023-06477-6
    7. James E. Barrett, Aryan Shekarabi, Saadet Inan. Oxycodone: A Current Perspective on Its Pharmacology, Abuse, and Pharmacotherapeutic Developments. Pharmacological Reviews 2023, 75 (6) , 1062-1118. https://doi.org/10.1124/pharmrev.121.000506
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    9. Joshua Barry, Katerina D. Oikonomou, Allison Peng, Daniel Yu, Chenyi Yang, Peyman Golshani, Christopher J. Evans, Michael S. Levine, Carlos Cepeda. Dissociable effects of oxycodone on behavior, calcium transient activity, and excitability of dorsolateral striatal neurons. Frontiers in Neural Circuits 2022, 16 https://doi.org/10.3389/fncir.2022.983323
    10. Ali AlArjani, Md Taufiq Nasseef, Sanaa M. Kamal, B. V. Subba Rao, Mufti Mahmud, Md Sharif Uddin. Application of Mathematical Modeling in Prediction of COVID-19 Transmission Dynamics. Arabian Journal for Science and Engineering 2022, 47 (8) , 10163-10186. https://doi.org/10.1007/s13369-021-06419-4
    11. Md Taufiq Nasseef, Weiya Ma, Jai Puneet Singh, Naoki Dozono, Kevin Lançon, Philippe Séguéla, Emmanuel Darcq, Hiroshi Ueda, Brigitte L. Kieffer. Chronic generalized pain disrupts whole brain functional connectivity in mice. Brain Imaging and Behavior 2021, 15 (5) , 2406-2416. https://doi.org/10.1007/s11682-020-00438-9
    12. Cherkaouia Kibaly, Jacob A. Alderete, Steven H. Liu, Hazem S. Nasef, Ping-Yee Law, Christopher J. Evans, Catherine M. Cahill. Oxycodone in the Opioid Epidemic: High ‘Liking’, ‘Wanting’, and Abuse Liability. Cellular and Molecular Neurobiology 2021, 41 (5) , 899-926. https://doi.org/10.1007/s10571-020-01013-y
    13. Richard J. Bodnar. Endogenous opiates and behavior: 2019. Peptides 2021, 141 , 170547. https://doi.org/10.1016/j.peptides.2021.170547
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    ACS Pharmacology & Translational Science

    Cite this: ACS Pharmacol. Transl. Sci. 2019, 2, 4, 264–274
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acsptsci.9b00021
    Published June 28, 2019
    Copyright © 2019 American Chemical Society
    Request reuse permissions

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