Thursday, December 26, 2024 12/26/2024

Pharmacology of opioid actions in vivo

Award Number: R01DA007242
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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View Award Abstract

Opiates remain among the most useful and important class of drugs in medicine, but not without problems. This submission proposes to examine two clinically relevant issues in opioid use – safety and tolerance. Most opioids used clinically act through the mu opioid receptor. The mu opioid receptor gene Oprm1 undergoes alternative splicing to generate a family of opioid receptors that can be categorized into three classes based upon their structure, each of which contain a number of variants. Knockout mouse models that selectively remove different sets of Oprm1 variants suggest that morphine acts through only one of these sets of variants while drugs acting through different sets of mu receptors lack respiratory depression, physical dependence and reward while maintaining their analgesic activity, thus enhancing their safety. The focus of this application is to understand the role and significance of the sets of mu opioid receptor splice variants in opioid analgesia, side-effects and tolerance. The current application will explore this concept by generating a mouse model in which selected opioid receptor splice variants can be expressed under native control of the Oprm1 gene, thereby permitting the exploration of their actions in vivo. The second aspect of this application involves tolerance. Preclinicla models reveal that short-term opioid administration leads to progressive tolerance. Yet, cancer patients can be maintained on fixed opioid doses without dose escalation to relieve their pain for many months. In a recent study using an extended chronic administration paradigm we reconciled these observations, showing a progressively increasing tolerance to morphine for up to three weeks that then stabilized with no further increases for as long as 6 weeks. Furthermore, this stabilization was associated with changes of select Oprm1 splice variants in specific brain regions of as much as 400-fold. The second component of this application will explore the stabilization of opioid tolerance with extended administration and potential mechanisms.


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: 2024 ( Subtotal = $0 )
2024	2022	RUTGERS, THE STATE UNIVERSITY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Drug Use and Addiction Research Programs	000	30	1/16/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $5,090 )
2023	2019	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10065	NEW YORK	USA	Drug Use and Addiction Research Programs	000	26	11/23/2022	NON-COMPETING CONTINUATION	$5,090
														Subtotal = $5,090

Issue Date FY: 2022 ( Subtotal = $361,100 )
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Drug Use and Addiction Research Programs	000	30	5/17/2022	NON-COMPETING CONTINUATION	$361,100
2022	2020	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Drug Use and Addiction Research Programs	002	27	5/17/2022	NON-COMPETING CONTINUATION	-$32,628
2022	2020	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Drug Use and Addiction Research Programs	003	28	5/17/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$125,841
2022	2019	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Drug Use and Addiction Research Programs	001	26	5/17/2022	NON-COMPETING CONTINUATION	-$93,213
														Subtotal = $361,100

Issue Date FY: 2021 ( Subtotal = $310,916 )
2021	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Drug Use and Addiction Research Programs	002	29	5/12/2021	NON-COMPETING CONTINUATION	$360,909
2021	2020	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Drug Use and Addiction Research Programs	000	27	11/17/2020	NON-COMPETING CONTINUATION	-$380,452
2021	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Drug Use and Addiction Research Programs	001	28	11/17/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$330,459
														Subtotal = $310,916

Issue Date FY: 2020 ( Subtotal = $413,080 )
2020	2020	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Drug Use and Addiction Research Programs	000	27	5/18/2020	NON-COMPETING CONTINUATION	$413,080
														Subtotal = $413,080

Issue Date FY: 2019 ( Subtotal = $413,080 )
2019	2019	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Drug Use and Addiction Research Programs	001	26	5/17/2019	NON-COMPETING CONTINUATION	$413,080
2019	2018	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Drug Use and Addiction Research Programs	000	25	4/9/2019	COMPETING CONTINUATION	$0
														Subtotal = $413,080

Issue Date FY: 2018 ( Subtotal = $394,910 )
2018	2018	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Drug Use and Addiction Research Programs	000	25	6/29/2018	COMPETING CONTINUATION	$394,910
														Subtotal = $394,910

Issue Date FY: 2017 ( Subtotal = -$1,389 )
2017	2014	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Drug Use and Addiction Research Programs	000	24	9/7/2017	NON-COMPETING CONTINUATION	-$1,389
														Subtotal = -$1,389

Issue Date FY: 2016 ( Subtotal = $0 )
2016	2014	SLOAN KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10021	NEW YORK	USA	Drug Use and Addiction Research Programs	000	24	4/18/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2014 ( Subtotal = $439,786 )
2014	2014	SLOAN KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10065	NEW YORK	USA	Drug Use and Addiction Research Programs	000	24	7/23/2014	NON-COMPETING CONTINUATION	$439,786
														Subtotal = $439,786

Issue Date FY: 2013 ( Subtotal = $422,195 )
2013	2013	SLOAN KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10065	NEW YORK	USA	Drug Use and Addiction Research Programs	001	23	5/16/2013	NON-COMPETING CONTINUATION	$26,387
2013	2013	SLOAN KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10065	NEW YORK	USA	Drug Use and Addiction Research Programs	000	23	4/19/2013	NON-COMPETING CONTINUATION	$395,808
														Subtotal = $422,195

Issue Date FY: 2012 ( Subtotal = $439,786 )
2012	2012	SLOAN KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10065	NEW YORK	USA	Drug Use and Addiction Research Programs	000	22	4/18/2012	NON-COMPETING CONTINUATION	$439,786
														Subtotal = $439,786

Issue Date FY: 2011 ( Subtotal = $448,854 )
2011	2011	SLOAN KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10065	NEW YORK	USA	Drug Use and Addiction Research Programs	000	21	5/2/2011	NON-COMPETING CONTINUATION	$448,854
														Subtotal = $448,854

Issue Date FY: 2010 ( Subtotal = $405,663 )
2010	2010	SLOAN KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10065	NEW YORK	USA	Drug Use and Addiction Research Programs	000	20	3/5/2010	COMPETING CONTINUATION	$405,663
														Subtotal = $405,663

Issue Date FY: 2009 ( Subtotal = $437,852 )
2009	2009	SLOAN KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10065	NEW YORK	USA	Drug Use and Addiction Research Programs	000	19	5/7/2009	NON-COMPETING CONTINUATION	$386,785
2009	2009	SLOAN KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10065	NEW YORK	USA	Drug Use and Addiction Research Programs	001	19	7/14/2009	NON-COMPETING CONTINUATION	$51,067
														Subtotal = $437,852

Issue Date FY: 2008 ( Subtotal = $386,785 )
2008	2008	SLOAN KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10021	NEW YORK	USA	Drug Use and Addiction Research Programs	000	18	5/21/2008	NON-COMPETING CONTINUATION	$386,785
														Subtotal = $386,785

Issue Date FY: 2007 ( Subtotal = $394,679 )
2007	2007	SLOAN KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10021	NEW YORK	USA	Drug Use and Addiction Research Programs	000	17	4/12/2007	NON-COMPETING CONTINUATION	$394,679
														Subtotal = $394,679

Issue Date FY: 2006 ( Subtotal = $361,305 )
2006	2006	SLOAN KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10021	NEW YORK	USA	Drug Use and Addiction Research Programs	000	16	5/1/2006	NON-COMPETING CONTINUATION	$361,305
														Subtotal = $361,305

Issue Date FY: 2005 ( Subtotal = $334,800 )
2005	2005	SLOAN KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10021	NEW YORK	USA	Drug Use and Addiction Research Programs	000	15	6/2/2005	COMPETING CONTINUATION	$334,800
														Subtotal = $334,800

Grand Total All Awards = $5,968,492

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Pharmacology of opioid actions in vivo

Award Number: R01DA007242

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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