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8/8 NADIA U01 Long-Term Effects of Adolescent Alcohol on Pain

Award Number: U01AA028709
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2020
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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8/8 NADIA U01 Long-Term Effects of Adolescent Alcohol on Pain - Adolescent alcohol use leads to persistent neural adaptations and behavioral dysregulation that increase the risk of developing alcohol use disorder (AUD). Acute alcohol reduces pain, and chronic pain (e.g., hyperalgesia) can promote alcohol drinking through negative reinforcing analgesic effects. Paradoxically, chronic alcohol produces hyperalgesia or worsen pre-existing pain states. Recently, we reported that medial central amygdala (CeA) projections to a midbrain region called the periaqueductal gray (vlPAG) are critical for mediating hyperalgesia in chronically alcohol exposed adult male rats. This chronic alcohol weakens synaptic connectivity between medial CeA and vlPAG in adult male rats, photostimulation of the CeA-vlPAG circuit rescues hyperalgesia in alcohol-dependent adult rats, and photoinhibition of this circuit produces hyperalgesia in naïve rats. Our lab and others find that antagonism of corticotropin-releasing factor type-1 receptors (CRFR1) in CeA reduces hyperalgesia associated with alcohol withdrawal, nicotine withdrawal and traumatic stress in adult rats. Our overarching hypotheses are that chronic intermittent alcohol exposure in adolescent rats (AIE) produces persist long-term effects on polymodal (i.e., mechanical and thermal) hyperalgesia that is mediated by weakened CeA-vlPAG connectivity and increased CRFR1 signaling in CeA. The CRFR1 signaling gating of CeA-vlPAG function is important for mediating AIE-induced hyperalgesia. We include preliminary data showing that 1) AIE produces rapid and long-lasting thermal and mechanical hyperalgesia during adolescence and that this effect persists into adulthood (Fig. 1), 2) AIE reduces synaptic drive and excitatory/inhibitory ratio on vlPAG-projecting medial CeA neurons in adulthood (Fig. 3), 3) CRFR1 is expressed on vlPAG projecting cells (Fig. 2), and 4) validation data for a CRFR1:cre rat for CRFR1+ cell type- specific modulation of CeA outputs (Fig. 4). Because we also propose to challenge rats with a short-lasting inflammatory pain challenge in adulthood, we have also piloted dose-response effects of carrageenan on nociception in adult Wistar rats. Here, we propose aims that will test the hypotheses that AIE produces hyperalgesia during adolescence that persists into adulthood (Specific Aim 1), that AIE reduces synaptic drive and excitatory/inhibitory balance of synaptic transmission onto vlPAG-projecting CeA neurons via a CRFR1- dependent (Specific Aim 2), and that pharmacological, circuit-based, and epigenetic modulation of CRFR1+ PAG- projecting CeA neurons will rescue AIE-induced hyperalgesia and CeA-vlPAG circuit plasticity (Specific Aim 3). Importantly, we propose specific collaborations with Research Component 6 (PI:Chandler) and 5 (PI: Crews) along with the Epigenetics Core (PI: Pandey) of the NADIA consortium. This proposal focuses on testing adolescent alcohol effects on pain-related outcomes and aligns with the overall goal of the NADIA consortium to examine the effects of adolescent alcohol exposure on the adult organism.


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 = -$1 )
2026	2024	LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER NEW ORLEANS	433 BOLIVAR ST RM 619	NEW ORLEANS	LA	70112	ORLEANS	USA	Alcohol Research Programs	000	5	12/1/2025	NON-COMPETING CONTINUATION	-$1
														Subtotal = -$1

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER NEW ORLEANS	433 BOLIVAR ST RM 619	NEW ORLEANS	LA	70112	ORLEANS	USA	Alcohol Research Programs	000	5	5/12/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $367,500 )
2024	2024	LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER NEW ORLEANS	433 BOLIVAR ST RM 619	NEW ORLEANS	LA	70112	ORLEANS	USA	Alcohol Research Programs	001	5	8/12/2024	NON-COMPETING CONTINUATION	$367,500
2024	2023	LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER NEW ORLEANS	433 BOLIVAR ST RM 619	NEW ORLEANS	LA	70112	ORLEANS	USA	Alcohol Research Programs	000	4	5/7/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $367,500

Issue Date FY: 2023 ( Subtotal = $367,500 )
2023	2023	LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER-NEW ORLEANS	433 BOLIVAR ST STE 815	NEW ORLEANS	LA	70112	ORLEANS	USA	Alcohol Research Programs	000	4	8/18/2023	NON-COMPETING CONTINUATION	$367,500
														Subtotal = $367,500

Issue Date FY: 2022 ( Subtotal = $367,500 )
2022	2022	LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER-NEW ORLEANS	433 BOLIVAR ST STE 815	NEW ORLEANS	LA	70112	ORLEANS	USA	Alcohol Research Programs	000	3	7/26/2022	NON-COMPETING CONTINUATION	$367,500
														Subtotal = $367,500

Issue Date FY: 2021 ( Subtotal = $367,500 )
2021	2021	LOUISIANA STATE UNIVERSITY SYSTEM	433 BOLIVAR ST STE 815	NEW ORLEANS	LA	70112	ORLEANS	USA	Alcohol Research Programs	000	2	8/23/2021	NON-COMPETING CONTINUATION	$367,500
														Subtotal = $367,500

Issue Date FY: 2020 ( Subtotal = $367,500 )
2020	2020	LOUISIANA STATE UNIVERSITY SYSTEM	433 BOLIVAR ST STE 815	NEW ORLEANS	LA	70112	ORLEANS	USA	Alcohol Research Programs	001	1	9/15/2020	NEW	$0
2020	2020	LOUISIANA STATE UNIVERSITY SYSTEM	433 BOLIVAR ST STE 815	NEW ORLEANS	LA	70112	ORLEANS	USA	Alcohol Research Programs	000	1	7/31/2020	NEW	$367,500
														Subtotal = $367,500

Grand Total All Awards = $1,837,499

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8/8 NADIA U01 Long-Term Effects of Adolescent Alcohol on Pain

Award Number: U01AA028709

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 09/01/2020

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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