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Regulation Of Opioid Receptor Signaling by Endogenous Peptides

Award Number: R01DA008863
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/15/1995
PERIOD OF PERFORMANCE END DATE: 01/31/2028

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Regulation Of Opioid Receptor Signaling by Endogenous Peptides - The current opioid epidemic highlights the need for a deeper understanding of how opioid receptors are activated in our body. Our knowledge about the downstream events following opioid receptor activation comes mainly from studies on opiates (e.g., morphine), synthetic drugs (e.g., fentanyl), and modified peptides (e.g., DAMGO). While these studies are important, the physiological ligands of the opioid receptors are endogenous opioid peptides such as endorphins, enkephalins, and dynorphins. Over 20 different opioid peptides have been identified in the brain, all of which activate the three types of opioid receptors (µOR, dOR, kOR) albeit with different affinities and efficacies for G protein-mediated versus β-arrestin-mediated signaling pathways. Thus, endogenous opioid peptides show biased agonism, a property previously found for opiates and synthetic opioids. Recent efforts to design safer opioid drugs were focused on optimizing G protein-mediated over β-arrestin- mediated pathways. However, this is overly simplistic because respiratory depression and other negative side effects of opioids have been shown to be G protein-dependent. Also, the model does not consider the possibility that ligands can preferentially activate different subtypes of G proteins and downstream mediators. Another factor that contributes to divergent signaling is agonist-mediated post endocytic signaling after receptor trafficking to endosomes followed either by lysosomal degradation versus recycling to the cell surface. Because endogenous opioid peptides are widely considered to be less toxic than opioid drugs, it is important to know the signaling properties of these peptides in comparison to representative opioid drugs. In this application we describe studies to characterize signaling by opioid peptides at individual receptor types. Based on preliminary data we hypothesize that “each opioid peptide exhibits a distinct signaling profile at each receptor type resulting in the expansion of opioid receptor signaling repertoire”. To test the hypothesis, in Aim 1 we will investigate the specific signaling pathways activated by individual opioid peptides and compare them to a selected set of opioid drugs that range in addiction potential and toxicity. In Aim 2 we will examine receptor trafficking and endosomal signaling upon activation by individual opioid peptides in comparison with a selected set of opioid drugs. In both Aims we utilize a combination of classic and modern techniques to study the effect of opioid peptides on cell lines expressing defined opioid receptors and signaling proteins, followed by electrophysiological analysis of brain regions important for rewarding effects (ventral tegmental area) and toxicity such as respiratory depression (the Kölliker Fuse nucleus). Together, these studies will broaden our understanding of opioid receptor signaling in response to their biological ligands, laying the groundwork for safer novel therapeutics for the treatment of pain, substance use disorders, and other disorders that involve the endogenous opioid system.


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 = $588,331 )
2026	2026	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Drug Use and Addiction Research Programs	000	31	1/28/2026	NON-COMPETING CONTINUATION	$529,498
2026	2026	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Drug Use and Addiction Research Programs	001	31	2/6/2026	NON-COMPETING CONTINUATION	$58,833
														Subtotal = $588,331

Issue Date FY: 2025 ( Subtotal = $588,309 )
2025	2025	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Drug Use and Addiction Research Programs	001	30	4/10/2025	NON-COMPETING CONTINUATION	$58,830
2025	2025	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Drug Use and Addiction Research Programs	000	30	1/9/2025	NON-COMPETING CONTINUATION	$529,479
														Subtotal = $588,309

Issue Date FY: 2024 ( Subtotal = $693,544 )
2024	2024	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Drug Use and Addiction Research Programs	001	29	1/25/2024	NON-COMPETING CONTINUATION	$539,317
2024	2024	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Drug Use and Addiction Research Programs	002	29	4/24/2024	NON-COMPETING CONTINUATION	$59,924
2024	2023	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Drug Use and Addiction Research Programs	000	28	12/13/2023	COMPETING CONTINUATION	$94,303
														Subtotal = $693,544

Issue Date FY: 2023 ( Subtotal = $633,725 )
2023	2023	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Drug Use and Addiction Research Programs	000	28	3/31/2023	COMPETING CONTINUATION	$633,725
														Subtotal = $633,725

Issue Date FY: 2012 ( Subtotal = $0 )
2012	2011	MT SINAI SCHOOL OF MEDICINE	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Drug Use and Addiction Research Programs	000	17	4/23/2012	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2011 ( Subtotal = $366,235 )
2011	2011	MT SINAI SCHOOL OF MEDICINE	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Drug Use and Addiction Research Programs	001	17	5/27/2011	NON-COMPETING CONTINUATION	$26,430
2011	2011	MT SINAI SCHOOL OF MEDICINE	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Drug Use and Addiction Research Programs	000	17	3/25/2011	NON-COMPETING CONTINUATION	$339,805
														Subtotal = $366,235

Issue Date FY: 2010 ( Subtotal = $377,561 )
2010	2010	MT SINAI SCHOOL OF MEDICINE	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK	NY	10029	NEW YORK	USA	Drug Use and Addiction Research Programs	000	16	3/31/2010	NON-COMPETING CONTINUATION	$377,561
														Subtotal = $377,561

Issue Date FY: 2009 ( Subtotal = $381,375 )
2009	2009	MT SINAI SCHOOL OF MEDICINE	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK	NY	10029	NEW YORK	USA	Drug Use and Addiction Research Programs	000	15	4/13/2009	NON-COMPETING CONTINUATION	$381,375
														Subtotal = $381,375

Issue Date FY: 2008 ( Subtotal = $376,371 )
2008	2008	MT SINAI SCHOOL OF MEDICINE	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Drug Use and Addiction Research Programs	000	14	2/22/2008	COMPETING CONTINUATION	$376,371
														Subtotal = $376,371

Issue Date FY: 2006 ( Subtotal = $331,034 )
2006	2006	MT SINAI SCHOOL OF MEDICINE	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Drug Use and Addiction Research Programs	000	13	3/22/2006	NON-COMPETING CONTINUATION	$331,034
														Subtotal = $331,034

Issue Date FY: 2005 ( Subtotal = $339,000 )
2005	2005	MT SINAI SCHOOL OF MEDICINE	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Drug Use and Addiction Research Programs	000	12	3/14/2005	NON-COMPETING CONTINUATION	$339,000
														Subtotal = $339,000

Issue Date FY: 2004 ( Subtotal = $339,000 )
2004	2004	MT SINAI SCHOOL OF MEDICINE	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Drug Use and Addiction Research Programs	000	11	3/22/2004	NON-COMPETING CONTINUATION	$339,000
														Subtotal = $339,000

Issue Date FY: 2003 ( Subtotal = $339,000 )
2003	2003	MT SINAI SCHOOL OF MEDICINE	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Drug Use and Addiction Research Programs	000	10		NON-COMPETING CONTINUATION	$339,000
														Subtotal = $339,000

Issue Date FY: 2002 ( Subtotal = $331,360 )
2002	2002	NEW YORK UNIVERSITY MEDICAL CENTER	550 1ST AVE, SC-2 KIPS BAY BG	NEW YORK	NY	10016	NEW YORK	USA	Drug Use and Addiction Research Programs	000	8	4/26/2002	COMPETING CONTINUATION	$331,360
														Subtotal = $331,360

Issue Date FY: 2001 ( Subtotal = $232,641 )
2001	2001	NEW YORK UNIVERSITY MEDICAL CENTER	550 1ST AVE, SC-2 KIPS BAY BG	NEW YORK	NY	10016	NEW YORK	USA	Drug Use and Addiction Research Programs	000	7	5/11/2001	NON-COMPETING CONTINUATION	$232,641
														Subtotal = $232,641

Issue Date FY: 2000 ( Subtotal = $227,545 )
2000	2000	NEW YORK UNIVERSITY MEDICAL CENTER	550 1ST AVE, SC-2 KIPS BAY BG	NEW YORK	NY	10016	NEW YORK	USA	Drug Use and Addiction Research Programs	000	6	5/22/2000	NON-COMPETING CONTINUATION	$227,545
														Subtotal = $227,545

Issue Date FY: 1999 ( Subtotal = $220,915 )
1999	1999	NEW YORK UNIVERSITY MEDICAL CENTER	550 1ST AVE, SC-2 KIPS BAY BG	NEW YORK	NY	10016	NEW YORK	USA	Drug Use and Addiction Research Programs	000	5	5/26/1999	NON-COMPETING CONTINUATION	$220,915
														Subtotal = $220,915

Issue Date FY: 1998 ( Subtotal = $219,755 )
1998	1998	NEW YORK UNIVERSITY MEDICAL CENTER	550 1ST AVE, SC-2 KIPS BAY BG	NEW YORK	NY	10016	NEW YORK	USA	Drug Use and Addiction Research Programs	000	4	7/21/1998	COMPETING CONTINUATION	$219,755
														Subtotal = $219,755

Grand Total All Awards = $6,585,701

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Regulation Of Opioid Receptor Signaling by Endogenous Peptides

Award Number: R01DA008863

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/15/1995

PERIOD OF PERFORMANCE END DATE: 01/31/2028

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