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Role of NK-1 receptors in descending modulation and ascending transmission of itch

Award Number: R01AR076434
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/05/2020
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Role of NK-1 receptors in descending modulation and ascending transmission of itch - Project Summary Itchy skin conditions affect a substantial portion of the US population at annual costs exceeding $100 billion. Most types of chronic itch are poorly managed, establishing a compelling need to develop more effective mechanisms-based treatments for these debilitating conditions. The present proposal will investigate the role of neurons located in the rostral ventromedial medulla (RVM) that express the receptor for substance P (i.e., NK-1R) in descending modulation of itch, as well as the role of NK-1R-expressing neurons in the superficial spinal and medullary dorsal horn in the ascending transmission of itch. The proposal has two overarching aims. Specific Aim 1 hypothesizes that NK-1R-expressing neurons, and specifically ON-cells in the RVM (i.e., those that fire just prior to a noxious stimulus-evoked withdrawal response), are critically involved in descending inhibition of spinal itch transmission. We will employ chemogenetic and intracranial microinjection approaches to test if activation of NK-1R-expressing RVM neurons suppresses acute pruritogen-evoked itch behavior, or manifestations of chronic itch (spontaneous and touch-evoked scratching) in mouse models of psoriasis and atopic dermatitis itch. We will also investigate NK- 1R-mediated descending inhibition of spinal itch-transmitting neurons. Finally, we will record from optogenetically identified NK-1R-expressing neurons in RVM and functionally establish if they are ON cells. Specific Aim 2 hypothesizes that NK-1R-expressing neurons in the superficial spinal/ medullary dorsal horn give rise to ascending projections to the somatosensory thalamus and parabrachial nucleus that are critically involved in transmitting itch-related signals. We will use an optogenetic approach to determine if NK-1R- expressing neurons in the spinal/medullary dorsal horn are activated by pruritogenic stimuli, and opto- and chemogenetic approaches to investigate if the activation of such neurons elicits behavioral signs of itch (and/or pain). A better understanding of central itch modulation and ascending sensory transmission has translational significance for developing novel antipruritic treatments targeting NK-1 receptors to increase descending inhibition of itch and reduce ascending itch-related signals. Page 1


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 = $324,141 )
2024	2024	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	7/26/2024	NON-COMPETING CONTINUATION	$324,141
														Subtotal = $324,141

Issue Date FY: 2023 ( Subtotal = $335,187 )
2023	2023	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	8/1/2023	NON-COMPETING CONTINUATION	$335,187
														Subtotal = $335,187

Issue Date FY: 2022 ( Subtotal = $332,754 )
2022	2022	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	3	7/14/2022	NON-COMPETING CONTINUATION	$332,754
2022	2021	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	12/23/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $332,754

Issue Date FY: 2021 ( Subtotal = $326,850 )
2021	2021	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	7/13/2021	NON-COMPETING CONTINUATION	$326,850
														Subtotal = $326,850

Issue Date FY: 2020 ( Subtotal = $337,727 )
2020	2020	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	8/3/2020	NEW	$337,727
														Subtotal = $337,727

Grand Total All Awards = $1,656,659

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Role of NK-1 receptors in descending modulation and ascending transmission of itch

Award Number: R01AR076434

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/05/2020

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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