# Serotonin mechanisms in fentanyl-induced respiratory depression

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $459,424

## Abstract

Project Summary
Fentanyl and other ultrapotent synthetic opioids cause respiratory depression, a potentially fatal acute toxic
effect that is mediated by activation of mu opioid receptors. Naloxone, an antagonist of mu opioid receptors,
can reverse fentanyl-induced respiratory depression, but must compete with ultrapotent opioids for receptor
binding. A respiratory stimulant that acts independently of opioid receptors would be an appealing approach to
combat ultrapotent synthetic opioid poisoning. Serotonin generally provides a net stimulatory effect on
breathing due, in part, to 5HT2A/2C receptors in respiratory controlling areas in the brainstem. In addition, the
emerging interest in serotonergic psychedelics for the treatment of various neuropsychiatric disorders,
including opioid use disorder, has led to renewed interest in development of serotonin agents, particularly
targeting the 5HT2A receptor. Activation of 5HT2A receptors in the dorsolateral pons can counter opioid-
induced respiratory depression and microinjection studies implicate medullary raphe neurons, which produce
serotonin, in opioid-induced respiratory depression, but mechanisms for these effects are unknown. The
overall goal of this proposal is to fill a major void in our understanding of serotonergic mechanisms in fentanyl-
induced respiratory depression. We hypothesize that fentanyl interferes with serotonin mediated mechanisms
that support breathing, which can be reversed by activation of 5HT2A receptors. We will test this hypothesis at
the cellular, circuit and whole animal level using approaches that selectively identify and modulate serotonin
neurons. Aim 1 will determine the effect of fentanyl on medullary raphe serotonin neuron activity mediated by
pre- and/or post-synaptic opioid receptors by recording from genetically labeled serotonin neurons contained in
acute brain slices. The role of post-synaptic opioid receptors on serotonin neurons in fentanyl-induced
respiratory depression will be determined in awake behaving mice. Aim 2 will determine the cellular and
synaptic mechanisms by which 5HT2A receptors and endogenous serotonin neurons counter opioid inhibition
of dorsolateral pontine neurons using ex vivo electrophysiology and a unique arterially perfused
pontomedullary circuit preparation. Aim 3 will determine the effect of systemic 5HT2A/2C agonists on fentanyl-
induced respiratory depression alone and in combination with a sub-therapeutic dose of naloxone in awake
behaving mice. Together, this R01 project will improve our understanding of serotonin mechanisms in fentanyl-
induced respiratory depression that will inform how to best leverage the serotonin system to counter fentanyl
toxicity in future studies.

## Key facts

- **NIH application ID:** 10986157
- **Project number:** 1R01DA061320-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Erica Sawyer Levitt
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $459,424
- **Award type:** 1
- **Project period:** 2024-06-15 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10986157

## Citation

> US National Institutes of Health, RePORTER application 10986157, Serotonin mechanisms in fentanyl-induced respiratory depression (1R01DA061320-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10986157. Licensed CC0.

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