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Defining the descending pain modulatory circuit

Award Number: R01NS120486
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: 10/01/2022
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Defining the descending pain modulatory circuit - PROJECT SUMMARY The central nervous system has an intrinsic pain modulatory system that regulates nociceptive processing through descending projections from the brainstem to the spinal cord dorsal horn. The ventrolateral periaqueductal gray (vlPAG) integrates sensory information with input from higher cortical and subcortical areas, and sends projections to the rostral ventromedial medulla (RVM) that are relayed to the dorsal horn of the spinal cord. Both the vlPAG and RVM are heterogenous with respect to participating in multiple behavioral circuits. The proposed studies build on extensive previous work from the Heinricher laboratory that has defined the output from the RVM, showing that bidirectional pain control from this region is mediated by two physiologically defined cell classes, “ON-cells” and “OFF-cells,” that respectively facilitate and inhibit dorsal horn nociceptive transmission under different conditions. The Ingram laboratory has expertise studying opioid actions within the PAG and RVM, as well as adaptations in both areas with persistent inflammation. Proposed viral optogenetic strategies will map and define the vlPAG circuit that regulates RVM ON-cells involved in the facilitation of pain and elucidate underlying cellular mechanisms that shift the balance of RVM output from inhibition of pain to facilitation of pain with persistent inflammation. The combined expertise of the two laboratories will focus on identified PAG-RVM synapses using optogenetic stimulation of RVM terminals originating from the PAG. In vitro brain-slice recordings (Ingram lab) will examine the heterogeneity of PAG output to the RVM and PAG-RVM synapses, as well as cellular mechanisms of synaptic plasticity induced in persistent inflammation. These studies will use a fluorescent label for the μ-opioid receptor to differentiate presumed ON-cells from other classes in the slice to determine whether PAG terminals directly synapse on ON-cells, OFF-cells, or both, as well as what neurotransmitters are released. In vivo single-cell recording studies (Heinricher lab) will determine how inflammation-induced changes in PAG-RVM synapses control excitability of specific populations of RVM neurons and establish the link between these changes and pain behaviors. A better understanding of molecular, cellular, and circuit-level mechanisms that underlie pain is essential if we are to develop better treatments. By carefully mapping the descending projections from PAG to RVM during the development of persistent inflammation, and by tying these to defined RVM outputs and behavior, we can begin to determine the interactions in this complex network, and gain new insights into how pain-modulating systems are recruited and modulated in acute and chronic pain.


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: 2027 ( Subtotal = -$172,937 )
2027	2025	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	10/20/2026	NON-COMPETING CONTINUATION	-$172,937
														Subtotal = -$172,937

Issue Date FY: 2025 ( Subtotal = $620,163 )
2025	2025	THE REGENTS OF THE UNIV. OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	5/28/2025	NON-COMPETING CONTINUATION	$448,522
2025	2022	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	4/23/2025	NON-COMPETING CONTINUATION	$171,641
														Subtotal = $620,163

Issue Date FY: 2024 ( Subtotal = $439,118 )
2024	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	5/30/2024	NON-COMPETING CONTINUATION	$439,118
														Subtotal = $439,118

Issue Date FY: 2023 ( Subtotal = $286,616 )
2023	2023	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	004	4	6/1/2023	NON-COMPETING CONTINUATION	$458,257
2023	2022	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	4/5/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$531,693
2023	2022	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	2	5/15/2023	NON-COMPETING CONTINUATION	-$47,749
2023	2022	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	4/5/2023	NON-COMPETING CONTINUATION	-$531,693
2023	2021	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	1	5/15/2023	NEW	-$123,892
														Subtotal = $286,616

Issue Date FY: 2022 ( Subtotal = $579,442 )
2022	2022	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	6/30/2022	NON-COMPETING CONTINUATION	$579,442
														Subtotal = $579,442

Issue Date FY: 2021 ( Subtotal = $607,279 )
2021	2021	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	8/3/2021	NEW	$607,279
														Subtotal = $607,279

Grand Total All Awards = $2,359,681

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Defining the descending pain modulatory circuit

Award Number: R01NS120486

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: 10/01/2022

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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