# Endocannabinoid Targeting for Opioid Induced Respiratory Depression

> **NIH NIH R01** · UNIVERSITY OF ARIZONA · 2022 · $1,648,561

## Abstract

Project Summary
Accidental overdoses fatalities define the opioid epidemic despite research efforts for alternative means to
address Opioid Use Disorder [1] and alternative chronic pain therapies [2]. The Centers for Disease Control
report over 400,000 lives lost since 1999 and more than 130 people lose their life to an accidental overdose daily
[3]. This number will continue to climb with excessive utilization of prescription opioids and the presence of
stronger synthetic opioids in the illicit market [4-6]. A potentially fatal opioid overdose can be successfully
reversed with naloxone, mu opioid receptor antagonist, [7], but with the number of pain patients rising above
heart disease and diabetes [2] and the increased presence of fentanyl in the illicit opioid market, adequate
distribution of naloxone to reverse an overdose before oxygen deprivation occurs remains difficult [8]. Attempts
to reduce opioid overdoses with novel opioid-like compounds have been largely unsuccessful [9]. Therefore, it
is essential that unexplored therapeutic strategies to prevent opioid-induced respiratory depression be
discovered.
Fatal opioid overdoses are typically attributed to respiratory depression, during which neurons within the
preBötzinger complex (pBc) in the brainstem that control reflexive inspiration are inhibited. Our pilot data suggest
that 1) the pBc contains the components of the endocannabinoid system, including the cannabinoid receptor 2
(CB2R), 2) CB2R activation by endogenous cannabinoid system (ECBS) lipids is critical to normal respiration
control, and 3) exogenous application of a CB2R agonist mitigates morphine induced respiratory depression.
The current proposal will build upon these findings, using behavioral pharmacology, whole body
plethysmography, imaging, molecular biology, analytical chemistry, and gene-editing to test the hypothesis that
endogenous cannabinoid levels in the pBc are reduced during opioid induced respiratory depression
(OIRD) and that administration of a brain penetrant CB2R agonist will mitigate OIRD. Aim 1 will test CB2R
agonism as a strategy to mitigate to OIRD. Each aim contains rationally designed studies that include sex
differences through inclusion of male and female mice, application to both acute and chronic use of medicinal
and recreational opioids (fentanyl, oxycodone, and heroin), and multiple chemical classes of CB2R agonists to
prevent and reverse OIRD. Aim 2 will determine levels of endocannabinoid lipids, enzymes, and receptors in
the preBotzinger complex (pBc) during OIRD. Successful completion of proposed studies will serve to
enhance our knowledge of the role of ECBS within the pBc in during normal respiration and during OIRD
and validate targeting the CB2R as a safe treatment therapeutic to reduce opioid overdoses.

## Key facts

- **NIH application ID:** 10508272
- **Project number:** 1R01DA056608-01
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Tally Marie Milnes
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,648,561
- **Award type:** 1
- **Project period:** 2022-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10508272

## Citation

> US National Institutes of Health, RePORTER application 10508272, Endocannabinoid Targeting for Opioid Induced Respiratory Depression (1R01DA056608-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10508272. Licensed CC0.

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