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Circuit and Synaptic Mechanisms of Endocannabinoid-Opioid Crosstalk

Award Number: R01DA054368
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Circuit and Synaptic Mechanisms of Endocannabinoid-Opioid Crosstalk - Project Summary For the past decade, the use of opioids has risen dramatically in the United States and the disproportional increase in opioid dependence and overdose death has led to the current opioid crisis. Although different measures have been taken to reduce opioid overutilization for pain management, opioid use in clinics continues leading to dependence and overdose. In there is a compelling need for non-opioid use of pharmacological addition, for the significant number of people with opioid use disorder, pharmacological therapies to complement current treatments for opioid disorder. A major challenge is to develop new treatment strategies that can attenuate the rewarding aspects opioids while preserving their powerful analgesic properties. endocannabinoid (eCB) system serves as a potential target for the development of new treatments as a complement to opioid based treatments. Several lines of evidence suggest The functional interaction between the opioid and the eCB system at the level of neurochemical, neuroanatomical and molecular pathways. Our preliminary results find that indirectly enhancing levels of the endocannabinoid 2- AG levels through pharmacological inhibition of its catabolic enzyme, monoacylglycerol lipase (MAGL), attenuates the rewarding effects of morphine, while maintaining its analgesic effects. In this proposal we will dissect at a circuit, synaptic and molecular level how elevated 2-AG attenuates opioid reward. Recent studies have underscored the role of local GABAergic neuronal inputs from the rostromedial tegmental nucleus (RMTg) in regulating the ventral tegmental area (VTA), a key dopaminergic brain region involved in opioid reward. Opioids are thought to act by disinhibiting RMTg inhibition onto VTA dopamine neurons by activating presynaptic mu opioid receptors (MOR), subsequently increasing dopamine cell firing and nucleus accumbens (NAc) activity that drives reward. However, little is known about how cannabinoid receptors (CB1R) and MORs signal and crosstalk at these key synapses. Aim 1 will examine 2-AG mechanisms in the VTA on opioid reward behavior and its effect on NAc dynamics. Aim 2 will examine the role of CB1R and MOR in the RMTg→VTA projection on opioid reward behavior and NAc dynamics. Aim 3 will examine synaptic and molecular mechanisms of CB1R and MOR crosstalk to determine how enhancing 2-AG levels leads to blunted opioid reward.


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: 2025 ( Subtotal = $667,788 )
2025	2025	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1805 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Drug Use and Addiction Research Programs	003	5	6/18/2025	NON-COMPETING CONTINUATION	$667,788
2025	2023	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Drug Use and Addiction Research Programs	001	2	3/19/2025	NON-COMPETING CONTINUATION	-$370,348
2025	2023	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1805 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Drug Use and Addiction Research Programs	002	3	3/19/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$527,991
2025	2022	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Drug Use and Addiction Research Programs	000	1	3/19/2025	NEW	-$157,643
														Subtotal = $667,788

Issue Date FY: 2024 ( Subtotal = $595,297 )
2024	2024	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1805 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Drug Use and Addiction Research Programs	002	4	6/17/2024	NON-COMPETING CONTINUATION	$667,788
2024	2023	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1805 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Drug Use and Addiction Research Programs	001	3	4/9/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$312,159
2024	2023	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Drug Use and Addiction Research Programs	000	2	4/5/2024	NON-COMPETING CONTINUATION	-$384,650
														Subtotal = $595,297

Issue Date FY: 2023 ( Subtotal = $754,998 )
2023	2023	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Drug Use and Addiction Research Programs	000	2	6/9/2023	NON-COMPETING CONTINUATION	$754,998
														Subtotal = $754,998

Issue Date FY: 2022 ( Subtotal = $786,660 )
2022	2022	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Drug Use and Addiction Research Programs	001	1	9/26/2022	NEW	$0
2022	2022	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Drug Use and Addiction Research Programs	000	1	9/23/2022	NEW	$786,660
														Subtotal = $786,660

Grand Total All Awards = $2,804,743

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Circuit and Synaptic Mechanisms of Endocannabinoid-Opioid Crosstalk

Award Number: R01DA054368

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/30/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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