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Opioid Modulation of Serotonin Neurons that Influence Breathing

Award Number: F31DA066153
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 10/07/2026
PERIOD OF PERFORMANCE END DATE: 10/06/2027

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Opioid Modulation of Serotonin Neurons that Influence Breathing - PROJECT ABSTRACT Opioids are the primary driver of drug overdose in the United States. Opioids like fentanyl exhibit toxicity by depressing breathing through activation of the mu-opioid receptor (MOR), which can cause fatality in overdose. Despite this, the neural mechanisms of opioid-induced respiratory depression (OIRD) are poorly understood. Furthermore, naloxone, the current standard of care for reversing OIRD, precipitates withdrawal and uncontrolled pain and can fail to reverse OIRD following large doses of opioids. The limitations of naloxone are due to its competitive mechanism at MOR, which could be addressed by obtaining a MOR-independent target. Brainstem serotonin (5-HT) plays a key role in stimulating breathing and could serve as a MOR-independent target for treating OIRD. Multiple 5-HT GPCR agonists have been shown to reverse OIRD in different mammalian models by complex, poorly understood means. Thus, the influence of opioids on brainstem 5-HT breathing circuitry and how 5-HT via a diverse group of receptors provides respiratory drive remains elusive. In preliminary experiments, optogenetic stimulation of caudal medullary raphe 5-HT neurons was sufficient to prevent OIRD, and these 5-HT neurons were influenced by presynaptic, but not postsynaptic, opioid receptors. A pontine respiratory center critical to OIRD, the lateral parabrachial area (LPB), receives serotonin inputs which could potentially reverse ORID. Therefore, the overall hypothesis of this proposal is that 5-HT neurons are regulated by MOR and their inputs to the LPB critically regulate respiratory drive under OIRD. This hypothesis will be tested at the cellular, circuit and whole animal level, providing rich training in multiple modern neuroscience techniques. Aim 1 will determine how opioids via MORs regulate medullary raphe 5-HT neurons using brain slice electrophysiology of fluorescently tagged neurons. Aim 2 will determine the role of LPB 5-HT signaling in OIRD using optogenetic activation of 5-HT neurons coupled with brain slice electrophysiology and in vivo measurements of breathing. The knowledge gained by this project will further the understanding of how opioids depress breathing and the mechanisms by which 5-HT acts as a respiratory stimulant. These findings have the potential to help guide the development of drugs for treating OIRD alone or in combination with naloxone. The training plan will provide additional career development training which is important for success in a career in biomedical research.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $44,158 )
2026	2026	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Drug Use and Addiction Research Programs	000	1	4/9/2026	NEW	$44,158
														Subtotal = $44,158

Grand Total All Awards = $44,158

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Opioid Modulation of Serotonin Neurons that Influence Breathing

Award Number: F31DA066153

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 10/07/2026

PERIOD OF PERFORMANCE END DATE: 10/06/2027

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