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Mapping brain-wide opioid actions by profiling neuronal activities and in vivo cellular target engagement

Award Number: R01DA059393
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2023
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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Mapping brain-wide opioid actions by profiling neuronal activities and in vivo cellular target engagement - Abstract Opioids are highly effective at reducing pain, but their potential for addiction and overdose has led to a growing public health crisis. Researchers have attempted to develop new opioid compounds that are less likely to be abused and have fewer side effects, but these efforts have been difficult. The endogenous opioid system has multiple receptors and ligands heterogeneously expressed across different parts of the body and cell types. Tremendous work has been done to delineate the relationships between opioid receptors (ORs) and ligands. However, the specificity of ligand-receptor engagement often depends on relative affinities at predetermined targets. In general, in vivo spatial and cellular heterogeneity of the brain obscure opioid actions, making them hard to predict based on receptor affinity alone. Currently, single-cell and spatial transcriptomics are transforming our understanding of brain architecture. However, there is a significant gap in how we measure opioid actions and align them with the spatially resolved cellular atlas of the brain. Levering emerging CATCH and inverse activity marker (IAM) techniques, we propose multimodal profiling of opioid actions with spatial and single-cell resolution across the entire mouse brain. Using three pharmacologically diverse opioids, we aim to map neuronal activities and cellular binding of these drugs onto the entire mouse brain in an unbiased way and register them with cell types identified from single-cell transcriptomics. Furthermore, we will test whether a drug’s affinities across different ORs determine its in vivo cell and neural ensemble engagement. Not only would this project provide a circuit-level mechanism linking the molecular pharmacology to brain-wide opioid actions, but also lay out a roadmap for evaluating and developing new opioids, e.g., by incorporating regional and cell-type preference into the structure-activity-relationship for lead optimization or by revealing on- and off-target sites to guide further cell-type specific in vitro chemical screening and optimization.


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 = $830,063 )
2026	2026	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Drug Use and Addiction Research Programs	000	4	6/23/2026	NON-COMPETING CONTINUATION	$830,063
														Subtotal = $830,063

Issue Date FY: 2025 ( Subtotal = $830,063 )
2025	2025	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Drug Use and Addiction Research Programs	000	3	7/8/2025	NON-COMPETING CONTINUATION	$830,063
														Subtotal = $830,063

Issue Date FY: 2024 ( Subtotal = $830,063 )
2024	2024	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Drug Use and Addiction Research Programs	000	2	7/1/2024	NON-COMPETING CONTINUATION	$830,063
														Subtotal = $830,063

Issue Date FY: 2023 ( Subtotal = $839,850 )
2023	2023	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Drug Use and Addiction Research Programs	000	1	9/20/2023	NEW	$839,850
														Subtotal = $839,850

Grand Total All Awards = $3,330,039

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Mapping brain-wide opioid actions by profiling neuronal activities and in vivo cellular target engagement

Award Number: R01DA059393

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/30/2023

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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