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Investigating opioid-induced dopamine rhythms and their role in respiratory suppression

Award Number: K99DA066035
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 05/15/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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Investigating opioid-induced dopamine rhythms and their role in respiratory suppression - Project Summary Opioid overdose, particularly from fentanyl, is the leading cause of drug-related deaths in the U.S., largely due to opioid-induced respiratory depression (OIRD). Tolerance to opioids' euphoric and analgesic effects develop faster than tolerance to their respiratory effects, increasing the risk of fatal overdose. Naloxone reverses respiratory depression but also blocks pain relief, highlighting the need for alternative therapies. This project describes the first reports of rhythmic dopamine release, produced after repeated high-dose fentanyl exposure, that may underlie the generation of agonal breathing responses. These “dopamine rhythms” originate in the ventral tegmental area (VTA) with each dopamine peak preceding inspiration. Mice exhibit a concomitant increase in both dopamine peak amplitude and agonal breathing response magnitude with each drug exposure. This proposal investigates the origin, function and molecular underpinnings of this possible “safety signal.” My preliminary data demonstrate that opioid-induced rhythmic dopamine release produces robust stereotyped peaks and is remarkably reproducible. To understand the role of these rhythms, I will employ optogenetic manipulations, patch clamp electrophysiology and single-cell RNA sequencing (scRNAseq) strategies. Based on my data thus far, I hypothesize that these dopamine rhythms have evolved to help maintain breathing under hypoxic stress. In Aim 1 (K99), I will delineate the causal relationship between the agonal breathing responses and the dopamine rhythms by optogenetically activating and inactivating the rhythmic signals. In Aim 2 (K99), I will use patch clamp electrophysiology to determine the molecular underpinnings in VTA dopamine and GABAergic neurons that may underlie the generation of these rhythms. Aim 3 (K99) will use scRNAseq to delineate cellular targets that may contribute to OIRD or opioid-use disorder generally. Finally, Aim 4 (R00) will use function-oriented synthesis to create novel chemical compounds to test the causal role of HCN channels in rhythm generation. Together, this proposal will define the role of these novel dopamine rhythms with breathing responses after repeated fentanyl administration. This project is conceptually novel, as it may represent a new function of the mesolimbic dopamine system in survival. In the K99 phase, I will be mentored by Dr. Robert Malenka, co-mentored by Dr. Karl Deisseroth, and will be advised by an exceptional advisory team composed of Dr. Boris Heifets, Dr. Ali Mohebi and Dr. Longzhi Tan. With their support and the tremendous scientific environment at Stanford University, I will gain technical training on optogenetics and scRNAseq, as well as refine my skills with patch clamp electrophysiology. This training will prepare me for my long-term goal of leading my own research laboratory where I will utilize advanced experimental techniques and a circuit-level approach complexed with my background in drug drug discovery to identify novel therapeutic targets for OIRD.


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 = $158,534 )
2026	2026	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Drug Use and Addiction Research Programs	000	1	5/14/2026	NEW	$158,534
														Subtotal = $158,534

Grand Total All Awards = $158,534

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Investigating opioid-induced dopamine rhythms and their role in respiratory suppression

Award Number: K99DA066035

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 05/15/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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