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Identifying new targets in pain, utilizing the novel analgesic AS1

Award Number: R01NS115747
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2020
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Identifying new targets in pain, utilizing the novel analgesic AS1 - Project Summary Pain is the number one reason patients seek health care and greater than 20% of the US population is affected by chronic pain. Existing therapeutics have limited efficacy and a narrow therapeutic period, while also evoking deleterious side effects. It is therefore vital to understand pain processing in order to develop novel therapeutics to address this pressing health care crisis. According to the International Association for the Study of Pain (IASP) pain is “an unpleasant sensory and emotional experience associated with actual or potential tissue damage”. Intrinsic to the emotional suffering elicited by pain perception is the attribution of a negative valence to nociceptive stimuli. Dysregulation of aversive motivational circuits may underlie much of the suffering associated with chronic pain conditions. Hedonic valence is a measurement of the intrinsic attractiveness (positive) or averseness (negative) of a stimulus. Pain typically has a negative valence, which is normally advantageous, driving self-protective behavior. Perversely, humans can sometimes assign a positive valence to nociceptive stimuli; think pleasure from spicy foods. This implies that the neural circuits that assign negative valence to nociceptive stimuli are malleable and that pain and aversion can be decoupled. Critically, there have been limited tools to investigate how valence is assigned to nociceptive stimuli by the nervous system. Here, we propose to investigate the effects on nociceptive processing by Analgesic Screen 1 (AS1), a small molecule we discovered that reverses the hedonic motivation (movement toward or away from) of nociceptive stimuli including heat and the noxious chemical allyl isothiocyanate (AITC) in larval zebrafish, rendering these highly aversive stimuli attractive or rewarding in a dose dependent manner. Remarkably, AS1 can tune the valence of nociceptive stimuli, transforming the valence from aversive to neutral to attractive. AS1 has no previously identified target or function. We hypothesize that AS1 potentiates the activity of the dopamine reward system via D1 receptor activation by promoting release of dopamine in the presence of nociceptive stimuli. Experiments in this proposal will make use of the unique advantages of the zebrafish and mouse model systems to test these hypotheses and when completed, we will have characterized the effects of AS1 on nociception and identified upon which neural circuits AS1 acts to invert the valence of nociceptive stimuli from aversive to attractive. In Aim 1, we propose to determine the effects of AS1 on aversion evoked by nociceptive and other aversive stimuli and how these stimuli alter neuronal activity in the CNS in the presence or absence of AS1 in zebrafish. In Aim 2, we will use a comprehensive genetic approach to assess the role of D1 receptor dependent dopaminergic signaling on aversion elicited by nociceptive stimuli in the presence or absence of AS1 in zebrafish. In Aim 3, we will ascertain the effect of AS1 on nociception, place aversion, whether these effects are dependent on D1 receptor activation and where AS1 effects neuronal activity in the CNS in response to nociceptive stimuli using the mouse model system.


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 = $336,644 )
2025	2025	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	12/5/2024	NON-COMPETING CONTINUATION	$336,644
														Subtotal = $336,644

Issue Date FY: 2024 ( Subtotal = $362,827 )
2024	2024	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	12/15/2023	NON-COMPETING CONTINUATION	$336,644
2024	2024	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	4/23/2024	NON-COMPETING CONTINUATION	$26,183
														Subtotal = $362,827

Issue Date FY: 2023 ( Subtotal = $374,047 )
2023	2023	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	12/2/2022	NON-COMPETING CONTINUATION	$336,644
2023	2023	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	1/31/2023	NON-COMPETING CONTINUATION	$37,403
														Subtotal = $374,047

Issue Date FY: 2022 ( Subtotal = $374,047 )
2022	2022	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	1/6/2022	NON-COMPETING CONTINUATION	$336,643
2022	2022	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	3/28/2022	NON-COMPETING CONTINUATION	$37,404
														Subtotal = $374,047

Issue Date FY: 2021 ( Subtotal = $396,335 )
2021	2021	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	11/24/2020	NEW	$396,335
														Subtotal = $396,335

Grand Total All Awards = $1,843,900

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Identifying new targets in pain, utilizing the novel analgesic AS1

Award Number: R01NS115747

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2020

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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