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Neuropeptidergic Inhibition of Spinal Pain Transmission

Award Number: R01NS045954
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: 09/10/2002
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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Neuropeptidergic Inhibition of Spinal Pain Transmission - Neuropathic pain (NP) is a debilitating disease that is difficult to manage. Current treatments are only partially effective, in a small subset of patients. The development of effective analgesics for NP is stalled by our incomplete understanding of its underlying mechanisms. An important clue comes from our progress on this project over the past 20 years with studies of the neurobiology of neuropeptide Y (NPY) and its inhibitory actions at excitatory interneurons (IN) in the dorsal horn of the spinal cord that express the NPY Y1 receptor (Y1). Our long-term goal is the development of Y1 agonists that will engage and inhibit precise subpopulations of Y1-INs and thus reduce NP. To this end, we confirmed that Y1-INs co-express either cholecystokinin (Cck), gastrin-releasing peptide (Grp), or Neuropeptide FF (Npff) mRNA, and that chemogenetic inhibition or ablation of Y1-IN blocked multiple signs of NP in mice with peripheral nerve injury. Similarly, chemogenetic inhibition of protein kinase C type γ interneurons (PKCγ-INs) reversed touch-evoked allodynia. Our central hypothesis is that nerve injury recruits a pronociceptive dorsal horn microcircuit that includes excitatory presynaptic input from PKCγ-IN onto the subpopulations of Y1-INs that facilitate neuropathic pain. Specific Aim 1 will use patch clamp dorsal horn slice electrophysiology to record postsynaptic currents, and high-resolution confocal microscopy to measure appositions between pre and postsynaptic elements of synapse, at Y1eGFP neurons. We predict that nerve injury will produce a net ratio increase not only in presynaptic excitatory vs inhibitory drive, but also in the number of excitatory vs inhibitory synapses, leading to a potentiation of neuronal activation in the CCK, GRP and/or Npff subpopulations of Y1- INs. Specific Aim 2 tests the hypothesis that Y1-INs are necessary and sufficient for neuropathic pain. We predict that wireless in vivo optogenetic activation of spinal Npy1rcre (Y1cre) neurons will produce nocifensive and aversive behaviors in normal mice, while optogenetic inhibition will reverse mechanical and cold allodynia in nerve-injured mice. Specific Aim 3 tests the hypothesis that nerve injury recruits a pronociceptive PKCγ  Y1-IN chronic pain circuit. We predict that chemogenetic or optogenetic activation of PKCγCreERT2 neurons will increase pERK+ immunoreactivity (a proxy for in vivo neuronal activity) and excitatory postsynaptic currents (EPSCs) in Y1eGFP reporter mice, while genetic inhibition of PKCγCreERT2 or pharmacological inhibition of PKCγ will prevent or reduce SNI potentiation of touch-evoked neuronal activation, spontaneous EPSCs and/or stimulus-evoked action potentials in Y1eGFP neurons. Specific Aim 4 will determine which subpopulations of excitatory Y1-INs are necessary for the antiallodynic actions of intrathecal Y1 agonists. We predict that conditional deletion of Y1 receptors in Lbx1cre spinal cord neurons as well as CckCre, GrpCre, and/or NpffCre neurons will prevent the ability of Y1 agonists to reduce SNI-induced allodynia, touch-evoked pERK, and A- fiber stimulus-evoked action potentials in Y1eGFP neurons.


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 = $447,613 )
2026	2026	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	21	12/16/2025	NON-COMPETING CONTINUATION	$447,613
														Subtotal = $447,613

Issue Date FY: 2025 ( Subtotal = $497,347 )
2025	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	20	8/5/2025	NON-COMPETING CONTINUATION	$49,734
2025	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	20	12/5/2024	NON-COMPETING CONTINUATION	$447,613
														Subtotal = $497,347

Issue Date FY: 2024 ( Subtotal = $482,428 )
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	19	4/25/2024	NON-COMPETING CONTINUATION	$34,815
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	19	12/5/2023	NON-COMPETING CONTINUATION	$447,613
														Subtotal = $482,428

Issue Date FY: 2023 ( Subtotal = $497,347 )
2023	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	18	2/8/2023	NON-COMPETING CONTINUATION	$497,347
														Subtotal = $497,347

Issue Date FY: 2022 ( Subtotal = $505,161 )
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	17	12/9/2021	COMPETING CONTINUATION	$505,161
2022	2021	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	16	6/15/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $505,161

Issue Date FY: 2021 ( Subtotal = $451,283 )
2021	2021	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	16	1/28/2021	NON-COMPETING CONTINUATION	$45,128
2021	2021	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	16	12/18/2020	NON-COMPETING CONTINUATION	$406,155
														Subtotal = $451,283

Issue Date FY: 2020 ( Subtotal = $451,345 )
2020	2020	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	15	11/27/2019	NON-COMPETING CONTINUATION	$406,212
2020	2020	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	15	2/20/2020	NON-COMPETING CONTINUATION	$45,133
														Subtotal = $451,345

Issue Date FY: 2019 ( Subtotal = $451,406 )
2019	2019	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	005	14	1/25/2019	NON-COMPETING CONTINUATION	$23,409
2019	2019	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	004	14	1/22/2019	NON-COMPETING CONTINUATION	$427,997
2019	2018	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	13	11/29/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$330,180
2019	2018	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	13	12/4/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$22,703
2019	2018	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	12	12/4/2018	NON-COMPETING CONTINUATION	-$22,703
2019	2018	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	12	11/29/2018	NON-COMPETING CONTINUATION	-$330,180
														Subtotal = $451,406

Issue Date FY: 2018 ( Subtotal = $427,997 )
2018	2018	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	12	4/24/2018	NON-COMPETING CONTINUATION	$42,799
2018	2018	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	12	11/24/2017	NON-COMPETING CONTINUATION	$385,198
														Subtotal = $427,997

Issue Date FY: 2017 ( Subtotal = $440,622 )
2017	2017	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	11	12/8/2016	COMPETING CONTINUATION	$440,622
														Subtotal = $440,622

Issue Date FY: 2013 ( Subtotal = $307,205 )
2013	2013	UNIVERSITY OF KENTUCKY, RESEARCH FOUNDATION	105 KINKEAD HALL	LEXINGTON	KY	40506	FAYETTE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	10	5/21/2013	NON-COMPETING CONTINUATION	$20,692
2013	2013	UNIVERSITY OF KENTUCKY, RESEARCH FOUNDATION	105 KINKEAD HALL	LEXINGTON	KY	40506	FAYETTE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	1/17/2013	NON-COMPETING CONTINUATION	$286,513
														Subtotal = $307,205

Issue Date FY: 2012 ( Subtotal = $303,127 )
2012	2012	UNIVERSITY OF KENTUCKY, RESEARCH FOUNDATION	105 KINKEAD HALL	LEXINGTON	KY	40506	FAYETTE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	2/6/2012	NON-COMPETING CONTINUATION	$303,127
														Subtotal = $303,127

Issue Date FY: 2011 ( Subtotal = $313,846 )
2011	2011	UNIVERSITY OF KENTUCKY, RESEARCH FOUNDATION	105 KINKEAD HALL	LEXINGTON	KY	40506	FAYETTE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	8	7/6/2011	NON-COMPETING CONTINUATION	$25,620
2011	2011	UNIVERSITY OF KENTUCKY, RESEARCH FOUNDATION	105 KINKEAD HALL	LEXINGTON	KY	40506	FAYETTE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	1/27/2011	NON-COMPETING CONTINUATION	$288,226
														Subtotal = $313,846

Issue Date FY: 2010 ( Subtotal = $341,469 )
2010	2010	UNIVERSITY OF KENTUCKY, RESEARCH FOUNDATION	105 KINKEAD HALL	LEXINGTON	KY	40506	FAYETTE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	1/19/2010	COMPETING CONTINUATION	$341,469
														Subtotal = $341,469

Issue Date FY: 2007 ( Subtotal = $208,600 )
2007	2007	TULANE UNIVERSITY OF LOUISIANA	6823 SAINT CHARLES STREET	NEW ORLEANS	LA	70118	ORLEANS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	4	3/12/2007	SUPPLEMENT FOR EXPANSION	$208,600
														Subtotal = $208,600

Issue Date FY: 2006 ( Subtotal = $74,250 )
2006	2006	TULANE UNIVERSITY OF LOUISIANA	6823 SAINT CHARLES STREET	NEW ORLEANS	LA	70118	ORLEANS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	1/31/2006	SUPPLEMENT FOR EXPANSION	$74,250
														Subtotal = $74,250

Issue Date FY: 2005 ( Subtotal = $282,150 )
2005	2005	TULANE UNIVERSITY OF LOUISIANA	6823 SAINT CHARLES STREET	NEW ORLEANS	LA	70118	ORLEANS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	8/11/2005	NON-COMPETING CONTINUATION	$282,150
														Subtotal = $282,150

Issue Date FY: 2004 ( Subtotal = $282,150 )
2004	2004	TULANE UNIVERSITY OF LOUISIANA	6823 SAINT CHARLES STREET	NEW ORLEANS	LA	70118	ORLEANS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	8/13/2004	NON-COMPETING CONTINUATION	$282,150
														Subtotal = $282,150

Issue Date FY: 2003 ( Subtotal = $282,150 ) (Continued on the next page)
Grand Total All Awards = $7,400,184

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Neuropeptidergic Inhibition of Spinal Pain Transmission

Award Number: R01NS045954

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: 09/10/2002

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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