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Angiotensin-converting enzyme governs endogenous opioid signaling and synaptic plasticity in nucleus accumbens

Brian H. Trieu, Bailey C. Remmers, Carlee Toddes, Dieter D. Brandner, Wei Xie, Swati S. More, View ORCID ProfilePatrick E. Rothwell
doi: https://doi.org/10.1101/2021.09.08.459469
Brian H. Trieu
1Graduate Program in Neuroscience, University of Minnesota Medical School; Minneapolis, USA
2Medical Scientist Training Program, University of Minnesota Medical School; Minneapolis, USA
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Bailey C. Remmers
3Department of Neuroscience, University of Minnesota Medical School; Minneapolis, USA
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Carlee Toddes
1Graduate Program in Neuroscience, University of Minnesota Medical School; Minneapolis, USA
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Dieter D. Brandner
1Graduate Program in Neuroscience, University of Minnesota Medical School; Minneapolis, USA
2Medical Scientist Training Program, University of Minnesota Medical School; Minneapolis, USA
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Wei Xie
4Center for Drug Design, College of Pharmacy, University of Minnesota; Minneapolis, USA
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Swati S. More
4Center for Drug Design, College of Pharmacy, University of Minnesota; Minneapolis, USA
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Patrick E. Rothwell
3Department of Neuroscience, University of Minnesota Medical School; Minneapolis, USA
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  • ORCID record for Patrick E. Rothwell
  • For correspondence: rothwell@umn.edu
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Abstract

Angiotensin-converting enzyme (ACE) regulates blood pressure by cleaving angiotensin I to produce angiotensin II. In the brain, ACE is expressed at uniquely high levels in the striatonigral pathway, but its central function remains poorly understood. We find that ACE degrades an unconventional enkephalin heptapeptide, Met-enkephalin-Arg-Phe, in the nucleus accumbens of mice. ACE inhibition enhanced mu opioid receptor activation by Met-enkephalin-Arg-Phe, causing a cell type-specific long-term depression of glutamate release onto medium spiny projection neurons expressing the Drd1 dopamine receptor. Systemic ACE inhibition was not intrinsically rewarding, but decreased the conditioned place preference caused by fentanyl administration, and enhanced reciprocal social interaction. Our results raise the enticing prospect that central ACE inhibition can boost endogenous opioid signaling for clinical benefit, while mitigating risk of addiction.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵† Contact information: 4-142 Wallin Medical Biosciences Building, 2101 6th Street SE, Minneapolis, MN, 55455; Phone: 612-626-8744

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Angiotensin-converting enzyme governs endogenous opioid signaling and synaptic plasticity in nucleus accumbens
Brian H. Trieu, Bailey C. Remmers, Carlee Toddes, Dieter D. Brandner, Wei Xie, Swati S. More, Patrick E. Rothwell
bioRxiv 2021.09.08.459469; doi: https://doi.org/10.1101/2021.09.08.459469
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Angiotensin-converting enzyme governs endogenous opioid signaling and synaptic plasticity in nucleus accumbens
Brian H. Trieu, Bailey C. Remmers, Carlee Toddes, Dieter D. Brandner, Wei Xie, Swati S. More, Patrick E. Rothwell
bioRxiv 2021.09.08.459469; doi: https://doi.org/10.1101/2021.09.08.459469

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