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Investigation of nociceptive endogenous opioid dynamics in the periaqueductal gray

Award Number: F32DA055458
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 02/03/2022
PERIOD OF PERFORMANCE END DATE: 02/02/2025

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Investigation of nociceptive endogenous opioid dynamics in the periaqueductal gray - PROJECT SUMMARY/ABSTRACT Chronic pain is a highly prevalent and debilitating clinical problem that negatively impacts the health and quality of life of millions of people. A common and relatively effective strategy to provide acute relief to chronic pain patients is through prescription of opioid compounds. However, opioid analgesics carry substantial abuse and overdose liabilities, contributing heavily to the ongoing opioid epidemic. These negative consequences of exogenous opioids result from their diffuse action at endogenous mu opioid receptor-expressing (MOR) brain regions beyond the pain-encoding neurocircuitry that they are intended to modulate. To meet the pressing demand for effective and safe analgesics, new, targeted pain therapies must be developed that emerge from focused research on the endogenous opioidergic cell types and neural circuits involved in pain perception (i.e., nociception) and opioid-induced analgesia. The ventrolateral periaqueductal gray (vlPAG) is critical in this regard as it can produce robust antinociception through MOR and the enkephalin peptides expressed by the cells and afferents it contains. Yet, long-standing questions remain concerning the endogenous opioid signaling dynamics in the vlPAG that are recruited by acute and chronic pain conditions. This proposal will begin to fill these gaps in knowledge with a combination of novel tools: genetic recombination in defined neural populations, MOR specific promoter viruses, and a fluorescent enkephalin sensor. Combined, these approaches allow for unprecedented in vivo access to the pre- and postsynaptic components of endogenous opioid transmission in the vlPAG. Thus, I will test my central hypothesis that the vlPAG contains a functional nociceptive MOR-expressing ensemble that is modulated by enkephalin release from forebrain and local interneurons to produce antinociception. In Aim 1, I will use classical pain assays to identify the molecular identity and calcium signaling activity patterns of the nociceptive MOR-expressing neural ensemble in the vlPAG (vlPAGNoci/MOR). I will further determine the functional role of vlPAGNoci/MOR neurons in antinociception through optogenetic inhibition during acute and inflammatory pain states. In Aim 2, I will identify and manipulate two putative enkephalinergic inputs to the vlPAG, local vlPAG interneurons and long-range medial nucleus of the central amygdala (CeM) projections, to determine their respective contributions to nociception. How these enkephalingeric afferents interact with the MOR-expressing neurons in the vlPAG will also be determined. The results of these proposed experiments will advance our understanding of endogenous opioid signaling processes that are engaged and altered by acute and chronic pain conditions. By elucidating the components of the endogenous opioid circuitry of the vlPAG that produce analgesia, relief from chronic pain may be realized by future therapies that target this system while lacking the harmful addictive properties of current opioid drugs. Completion of this Fellowship proposal will achieve my training goals to expand my experimental expertise and establish myself as an expert in pain and opioidergic neurocircuitry.


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 = -$13,426 )
2026	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Drug Use and Addiction Research Programs	000	3	1/29/2026	NON-COMPETING CONTINUATION	-$13,426
														Subtotal = -$13,426

Issue Date FY: 2024 ( Subtotal = $81,592 )
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Drug Use and Addiction Research Programs	000	3	1/26/2024	NON-COMPETING CONTINUATION	$76,472
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Drug Use and Addiction Research Programs	001	3	5/1/2024	NON-COMPETING CONTINUATION	$5,120
														Subtotal = $81,592

Issue Date FY: 2023 ( Subtotal = $74,492 )
2023	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Drug Use and Addiction Research Programs	000	2	2/7/2023	NON-COMPETING CONTINUATION	$74,492
														Subtotal = $74,492

Issue Date FY: 2022 ( Subtotal = $70,282 )
2022	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Drug Use and Addiction Research Programs	003	1	5/23/2022	NEW	$1
2022	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Drug Use and Addiction Research Programs	002	1	4/21/2022	NEW	$1,587
2022	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Drug Use and Addiction Research Programs	001	1	1/11/2022	NEW	$0
2022	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Drug Use and Addiction Research Programs	000	1	1/11/2022	NEW	$68,694
														Subtotal = $70,282

Grand Total All Awards = $212,940

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Investigation of nociceptive endogenous opioid dynamics in the periaqueductal gray

Award Number: F32DA055458

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 02/03/2022

PERIOD OF PERFORMANCE END DATE: 02/02/2025

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