# Mechanisms of repeated opioid use dependent remodeling in respiratory control

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2022 · $643,700

## Abstract

PROJECT SUMMARY
Overdose deaths related to synthetic opioids have increased six-fold over the past 20 years. Repeated opioid
users, such as individuals suffering from substance use disorder, are at the greatest risk for opioid induced
respiratory depression, the hallmark of overdose. Although extensive understanding into the cellular, circuit and
pharmacological basis by which opioids suppress breathing exists, how repeated opioid use impacts the control
of breathing has been largely understudied. This is despite the clinical and laboratory evidence indicating that
repeated opioid use significantly changes the control of breathing. This knowledge gap contributes to the limited
ability to address opioid overdose among repeat opioid users—the population most vulnerable to overdose
death. Even among repeat opioid users, tolerance to opioid induced respiratory depression can be labile. It is
well-recognized that tolerance to the analgesic and euphoric effects of opioids has context-dependence.
Similarly, the susceptibility to opioid overdose can be influenced by the context in which these drugs are used.
Yet, the contribution of context-dependent mechanisms to the susceptibility of opioid induced respiratory
depression is unknown. We developed a model of repeated fentanyl use that produces changes in breathing
consistent with the breathing phenotype observed in repeated opioid users—including a form of tolerance
dependent on context. The primary objective of this proposal is to examine the mechanisms involved with
repeated opioid use-dependent remodeling in the control of breathing. We hypothesize that repeated opioid use
remodels the control of breathing through direct cellular changes in the respiratory network and through the
emergence of a labile form of tolerance dependent on behavioral conditioning and neuromodulation within the
respiratory network. This work will examine: (1) the cellular and the neurophysiological mechanisms that underlie
the remodeling of the control of breathing after repeated opioid use; (2) the contribution that learned behavior
has in producing state-dependent breathing and influencing opioid susceptibility; and (3) the role that
neuromodulation plays in influencing the stability of inspiratory drive prior to and after repeated opioid use. Thus,
this work provides a much-needed mechanistic framework for understanding how repeated opioid use remodels
the control of breathing. Such a framework can serve as a foundation for novel approaches and therapies to
address the risk of opioid overdose in individuals most vulnerable to overdose-death and respiratory-associated
co-morbidities.

## Key facts

- **NIH application ID:** 10539902
- **Project number:** 1R01HL163965-01A1
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Alfredo J Garcia
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $643,700
- **Award type:** 1
- **Project period:** 2022-08-05 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10539902

## Citation

> US National Institutes of Health, RePORTER application 10539902, Mechanisms of repeated opioid use dependent remodeling in respiratory control (1R01HL163965-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10539902. Licensed CC0.

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