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Endocannabinoid Metabolism in Acute Pain

Award Number: R01DA048002
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/15/2020
PERIOD OF PERFORMANCE END DATE: 02/28/2025

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Endocannabinoid Metabolism in Acute Pain - Project Summary Failure to adequately treat pain accounts for hundreds of billions of dollars of lost productivity and medical expenses annually. According to the Centers for Disease Control, each day in the United States over forty people die from an overdose of prescription pain killers (e.g. Vicodin and OxyContin). Consequently, there is an urgent need to develop new, safe, and potent non-opioid analgesics for the treatment of acute and chronic pain. Many surgical procedures induce significant acute pain that is difficult to treat. Patients who undergo such major surgical procedures are also at an increased risk of developing a subsequent opioid addiction. Therefore, improving acute pain control will not only enhance patient outcomes but may also lead to reduced prevalence of subsequent opioid abuse. The endocannabinoid 2-arachidonoylglycerol (2-AG) produces analgesia by activating cannabinoid receptors. However, 2-AG can also be hydrolyzed by the enzyme monoacylglycerol lipase (MAGL) to generate arachidonic acid, the precursor to downstream eicosanoids that can promote pain. In a recent publication, our group demonstrated that 2-AG levels were elevated in patients who developed greater acute postoperative pain, suggesting that 2-AG/eicosanoid crosstalk may directly modulate acute pain in humans. However, the contribution of 2-AG metabolism toward acute pain is poorly defined and its role in eicosanoid biosynthesis and pain in humans is lacking, highlighting a major gap in our understanding of endocannabinoid metabolism and pain. The current proposal leverages rodent surgical models and patient derived samples to test the major hypothesis that MAGL activity is essential for the biosynthesis of cyclooxygenase and 5-lipoxygenase (5-LOX) derived eicosanoids, which we hypothesize operate in parallel to promote acute pain. In Aim 1, we will employ complementary pharmacological and genetic approaches to test the hypothesis that MAGL inhibition suppresses acute pain by depriving cyclooxygenase and 5-LOX enzymes of arachidonic acid for eicosanoid biosynthesis within the incision site. This aim will also employ selective inhibitors and 5-LOX KO mice to test the hypothesis that 5-LOX inhibition attenuates acute pain. Aim 2 will leverage novel conditional MAGL knockout mice to identify peripheral cell populations wherein MAGL activity contributes to postoperative eicosanoid biosynthesis and pain. Aim 3 will characterize 2-AG/eicosanoid crosstalk in perioperative human tissue and will assess the contribution of 2-AG and eicosanoid levels toward acute pain in humans. The outcome of this study will provide fundamental insights into endocannabinoid/eicosanoid crosstalk and may identify MAGL as a novel target for the treatment of acute pain, thereby providing the foundation for the rapid translation of MAGL inhibitors to patients suffering from inadequately controlled pain.


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 = $461,057 )
2024	2024	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Drug Use and Addiction Research Programs	001	5	4/25/2024	NON-COMPETING CONTINUATION	$46,106
2024	2024	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Drug Use and Addiction Research Programs	000	5	2/15/2024	NON-COMPETING CONTINUATION	$414,951
														Subtotal = $461,057

Issue Date FY: 2023 ( Subtotal = $461,057 )
2023	2023	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Drug Use and Addiction Research Programs	000	4	2/10/2023	NON-COMPETING CONTINUATION	$461,057
														Subtotal = $461,057

Issue Date FY: 2022 ( Subtotal = $461,057 )
2022	2022	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Drug Use and Addiction Research Programs	001	3	3/21/2022	NON-COMPETING CONTINUATION	$46,107
2022	2022	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Drug Use and Addiction Research Programs	000	3	2/14/2022	NON-COMPETING CONTINUATION	$414,950
														Subtotal = $461,057

Issue Date FY: 2021 ( Subtotal = $461,057 )
2021	2021	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Drug Use and Addiction Research Programs	000	2	2/19/2021	NON-COMPETING CONTINUATION	$461,057
														Subtotal = $461,057

Issue Date FY: 2020 ( Subtotal = $461,057 )
2020	2020	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Drug Use and Addiction Research Programs	000	1	4/9/2020	NEW	$461,057
														Subtotal = $461,057

Grand Total All Awards = $2,305,285

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Endocannabinoid Metabolism in Acute Pain

Award Number: R01DA048002

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/15/2020

PERIOD OF PERFORMANCE END DATE: 02/28/2025

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