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The Nociceptin ORL1 System: Treatment Target for Relapse

Award Number: R01AA014351
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2004
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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The Nociceptin ORL1 System: Treatment Target for Relapse - Treatment with naltrexone (NTX), a nonselective µ, d, k (MOP, DOP, KOP) classical opioid receptor antagonist, is considered a gold standard of care for alcohol use disorder (AUD). Nonetheless, there is an urgent need for novel and more efficacious pharmacological approaches to AUD since only a minority of patients benefit from NTX. Findings of the previous funding periods suggest that both innate and chronic EtOH-induced overexpression of classical opioid receptors contribute to enhanced motivation for EtOH whereas activation of the antiopioid nociceptin/orphanin (N/OFQ) receptor (NOP) system reduces EtOH intake and seeking. Preliminary data supporting this renewal suggest that simultaneous blockade of classical opioid receptors with concurrent activation of NOP has superior efficacy compared to classical opioid receptor antagonists such as NTX or manipulation of single receptor subtypes. These findings provide a solid foundation for a systematic investigation of the therapeutic potential of a novel pharmacological agent (BU10119) that blocks MOP, DOP, and KOP receptors while activating NOP receptors. The major objective of this project, therefore, is to establish the efficacy of BU10119 (and, by inference, mixed nonselective classical opioid antagonists/NOP agonists) for AUD treatment as well as the neurobiological basis of BU10119’s actions. Specific Aim 1 will establish the effects of acute BU10119 vs. NTX on EtOH drinking and context or stress-induced EtOH seeking in rats with intact NOP function [nondependent Wistar rats (ndW)] compared to both rats with innate [Marchigian Sardinian alcohol preferring rats (msP)] and chronic EtOH-induced [(postdependent Wistar rats (pdW)] NOP overexpression and rats with deficient NOP function [NOP-knockout (NOP-KO) rats]. Specific Aim 2 is designed to characterize the effects of BU10119 in the context of chronic treatment. This objective is translationally relevant as well as necessary given the known sensitivity of N/OFQ-NOP function to adaptive changes with repeated pharmacological manipulation and will establish the direction in which such possible changes modify the effects of BU10119 vs. NTX. Specific Aim 3 will elucidate how recruitment of the N/OFQ system contributes to the efficacy BU10119 by establishing the effects of concurrent classical opioid receptor blockade and NOP activation and by identifying the brain site(s) in which NOP activation conveys enhanced efficacy to mixed MOP, DOP, KOP antagonists / NOP agonists. Successful completion of this project is expected (a) to define the therapeutic potential of drugs acting as classical opioid receptor antagonists / NOP agonists for AUD treatment while directly informing the development of BU10119 as an AUD therapeutic, and (b) to generate novel information on the neural basis of the “anti-addiction” effects of this class of pharmacological agents.


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 = $251,712 )
2026	2026	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	000	20	5/26/2026	NON-COMPETING CONTINUATION	$251,712
														Subtotal = $251,712

Issue Date FY: 2025 ( Subtotal = $346,968 )
2025	2025	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	000	19	8/13/2025	NON-COMPETING CONTINUATION	$346,968
														Subtotal = $346,968

Issue Date FY: 2024 ( Subtotal = $346,968 )
2024	2024	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	000	18	5/30/2024	NON-COMPETING CONTINUATION	$346,968
														Subtotal = $346,968

Issue Date FY: 2023 ( Subtotal = $342,864 )
2023	2023	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	000	17	5/24/2023	NON-COMPETING CONTINUATION	$342,864
														Subtotal = $342,864

Issue Date FY: 2022 ( Subtotal = $355,514 )
2022	2022	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	001	16	8/16/2022	COMPETING CONTINUATION	$355,514
2022	2020	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	000	15	4/26/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $355,514

Issue Date FY: 2020 ( Subtotal = $360,734 )
2020	2020	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	000	15	8/14/2020	NON-COMPETING CONTINUATION	$360,734
														Subtotal = $360,734

Issue Date FY: 2019 ( Subtotal = $360,734 )
2019	2019	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	000	14	8/14/2019	NON-COMPETING CONTINUATION	$360,734
														Subtotal = $360,734

Issue Date FY: 2018 ( Subtotal = $360,734 )
2018	2018	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	000	13	8/10/2018	NON-COMPETING CONTINUATION	$360,734
														Subtotal = $360,734

Issue Date FY: 2017 ( Subtotal = $486,509 )
2017	2017	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	000	12	8/2/2017	NON-COMPETING CONTINUATION	$360,734
2017	2017	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	001	12	9/7/2017	SUPPLEMENT FOR EXPANSION	$125,775
														Subtotal = $486,509

Issue Date FY: 2016 ( Subtotal = $380,169 )
2016	2016	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	000	11	9/22/2016	COMPETING CONTINUATION	$380,169
														Subtotal = $380,169

Issue Date FY: 2014 ( Subtotal = $366,101 )
2014	2014	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	000	10	8/1/2014	NON-COMPETING CONTINUATION	$366,101
														Subtotal = $366,101

Issue Date FY: 2013 ( Subtotal = $351,005 )
2013	2013	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	000	9	5/31/2013	NON-COMPETING CONTINUATION	$351,005
														Subtotal = $351,005

Issue Date FY: 2012 ( Subtotal = $377,424 )
2012	2012	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	000	8	5/25/2012	NON-COMPETING CONTINUATION	$377,424
														Subtotal = $377,424

Issue Date FY: 2011 ( Subtotal = $377,424 )
2011	2011	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	000	7	6/6/2011	NON-COMPETING CONTINUATION	$377,424
														Subtotal = $377,424

Issue Date FY: 2010 ( Subtotal = $414,010 )
2010	2010	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	000	6	7/12/2010	COMPETING CONTINUATION	$414,010
														Subtotal = $414,010

Issue Date FY: 2008 ( Subtotal = $349,121 )
2008	2008	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	000	5	5/29/2008	NON-COMPETING CONTINUATION	$349,121
														Subtotal = $349,121

Issue Date FY: 2007 ( Subtotal = $346,391 )
2007	2007	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	000	4	5/25/2007	NON-COMPETING CONTINUATION	$346,391
														Subtotal = $346,391

Issue Date FY: 2006 ( Subtotal = $356,735 )
2006	2006	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	000	3	5/23/2006	NON-COMPETING CONTINUATION	$356,735
														Subtotal = $356,735

Issue Date FY: 2005 ( Subtotal = $365,320 )
2005	2005	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	000	2	5/16/2005	NON-COMPETING CONTINUATION	$365,320
														Subtotal = $365,320

Issue Date FY: 2004 ( Subtotal = $387,245 )
2004	2004	SCRIPPS RESEARCH INSTITUTE, TPC 7	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	000	1	8/25/2004	NEW	$387,245
														Subtotal = $387,245

Grand Total All Awards = $7,283,682

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The Nociceptin ORL1 System: Treatment Target for Relapse

Award Number: R01AA014351

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2004

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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