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Determining the impact of BNST CRF systems on inflammatory pain-induced disruptions of behavior

Award Number: R01NS122230
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Determining the impact of BNST CRF systems on inflammatory pain-induced disruptions of behavior - Pain is currently the most common cause of long-term disability in the United States, affecting over 70 million Americans and 1.5 billion people worldwide. The first line of treatment for pain has been opioids, however their use is associated with addiction, dependence and overdose. A strategy for reducing the reliance on opioids for treatment of chronic pain is to better understand the circuits that mediate different aspects of chronic pain and identify non-opioidergic mechanisms to restore normal circuit function and behavior. Corticotropin releasing factor (CRF) signaling in the bed nucleus of the stria terminalis (BNST) has been shown to regulate both nociceptive and affective/motivational behaviors associated with pain, however the clinical utility of pharmacologically targeting the CRF system has yet to be explored. Given the critical need to develop treatments to target affective and motivational aspects of chronic pain, this could be an important path forward. We hypothesize that persistent inflammatory pain leads to increased activation of CRF signaling in the BNST leading to disrupted affective behaviors and reduced motivation. We posit that modulators of BNST function that oppose CRF signaling could provide a novel approach to investigate and treat both nociceptive and motivational/affective aspects of pain. Relevant to this, we have found in preliminary studies, a population of periaqueductal gray dopamine (PAGDA) neurons that project to the BNST that exhibit anti-nociceptive properties when activated, highlighting the possibility that dopamine in the BNST is a critical suppressor of pain-related behaviors. Previous studies have found that these PAGDA neurons play a key role in opioid induced anti-nociception. The objective of this proposal is to rigorously and mechanistically determine the role of the PAGDA to BNSTCRF circuit in inflammatory pain-driven changes in behavior, with the long term goal of identifying new treatments for inflammatory pain. We have collected strong data showing that acute pain engages this circuit, and hypothesize that this initial engagement leads to plasticity contributing to the persistence of inflammatory pain, and the development of emotional behaviors associated with inflammatory pain. This will be accomplished via three convergent aims


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 = $355,837 )
2025	2025	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	3/26/2025	NON-COMPETING CONTINUATION	$355,837
														Subtotal = $355,837

Issue Date FY: 2024 ( Subtotal = $383,512 )
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	4/10/2024	NON-COMPETING CONTINUATION	$27,675
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	3/27/2024	NON-COMPETING CONTINUATION	$355,837
														Subtotal = $383,512

Issue Date FY: 2023 ( Subtotal = $395,372 )
2023	2023	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	3/30/2023	NON-COMPETING CONTINUATION	$395,372
														Subtotal = $395,372

Issue Date FY: 2022 ( Subtotal = $417,304 )
2022	2022	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	4/12/2022	NON-COMPETING CONTINUATION	$417,304
														Subtotal = $417,304

Issue Date FY: 2021 ( Subtotal = $431,179 )
2021	2021	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	4/7/2021	NEW	$431,179
														Subtotal = $431,179

Grand Total All Awards = $1,983,204

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Determining the impact of BNST CRF systems on inflammatory pain-induced disruptions of behavior

Award Number: R01NS122230

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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