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Mechanism of Nociception Induced by Innocuous Cold in Trigeminal System

Award Number: R01DE018661
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/11/2008
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Mechanism of Nociception Induced by Innocuous Cold in Trigeminal System - ABSTRACT: Trigeminal neuropathic pain is the most debilitating pain disorder but current treatments including opiates are not effective for it in most patients. The pain can often be triggered by a breath of cooling air blowing on the face. Mechanisms of trigeminal neuropathic pain exacerbation at cooling temperatures are not well understood, which prevents us from designing mechanistically based therapy to effectively treat this devastating pain. Our recent studies in rat models have suggested that thermally sensitive two-pore domain K+ channels (thermal K2Ps) may play a key role in trigeminal neuropathic pain exacerbation at cooling temperatures. Our central hypotheses here are: 1) Thermal K2Ps provide a brake to prevent nociceptor hyperexcitability under physiological conditions, 2) Trigeminal nerve injury causes thermal K2P down- regulation to impair the brake leading to trigeminal nociceptor hyperexcitability and neuropathic pain, and 3) Cooling temperatures further suppress thermal K2Ps to lead to trigeminal neuropathic pain exacerbation. We will test these hypotheses with the following specific aims. ♦Aim 1. Elucidate the role of thermal K2Ps in controlling trigeminal nociceptor excitability and determine the effects of cooling temperatures on K2P functions. We will use immunohistochemistry to characterize thermal K2P expression in trigeminal nociceptors of normal rats. We will use our newly developed in situ patch-clamp recordings to characterize thermal K2P- mediated leak K+ currents in trigeminal nociceptors and their role in controlling trigeminal nociceptor excitability of normal rats. We will study effects of cooling temperatures on thermal K2P functions in trigeminal nociceptors of normal rats. ♦Aim 2. Elucidate that trigeminal nerve injury down-regulates thermal K2P expression leading to trigeminal nociceptor hyperexcitability. We will use two established rat models of trigeminal neuropathic pain, the infraorbital nerve chronic constrictive injury (ION-CCI) and oxaliplatin-induced trigeminal neuropathy models. We will study changes of thermal K2P expression and thermal K2P-mediated leak K+ currents in trigeminal nociceptors of these models. We will use pharmacological and genetic approaches to elucidate that down-regulation of thermal K2Ps leads to trigeminal nociceptor hyperexcitability. We will determine how cooling temperatures further exacerbate hyperexcitability of trigeminal nociceptors of these rat models. ♦Aim 3. Elucidate that thermal K2P down-regulation underlies trigeminal neuropathic pain, and establish thermal K2Ps as therapeutic targets for trigeminal neuropathic pain in rat models. We will use orofacial operant tests to study whether thermal K2P down-regulation leads to trigeminal neuropathic pain manifested with cold allodynia and hyperalgesia. We will use ION-CCI and oxaliplatin models to determine whether trigeminal neuropathic pain can be alleviated by pharmacological and genetic enhancements of thermal K2P functions in trigeminal afferent nerves. ♦ Completion of these Aims will fill the scientific gap of trigeminal nociception, elucidate a new mechanism of trigeminal neuropathic pain, and establish new therapeutic targets for this debilitating 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: 2024 ( Subtotal = $501,237 )
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Oral Diseases and Disorders Research	001	17	7/11/2024	NON-COMPETING CONTINUATION	$501,237
2024	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Oral Diseases and Disorders Research	000	16	2/15/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $501,237

Issue Date FY: 2023 ( Subtotal = $511,465 )
2023	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Oral Diseases and Disorders Research	000	16	7/28/2023	NON-COMPETING CONTINUATION	$511,465
														Subtotal = $511,465

Issue Date FY: 2022 ( Subtotal = $506,352 )
2022	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Oral Diseases and Disorders Research	000	15	8/26/2022	NON-COMPETING CONTINUATION	$506,352
														Subtotal = $506,352

Issue Date FY: 2021 ( Subtotal = $511,465 )
2021	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Oral Diseases and Disorders Research	002	14	7/20/2021	NON-COMPETING CONTINUATION	$511,465
2021	2020	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Oral Diseases and Disorders Research	001	13	5/21/2021	COMPETING CONTINUATION	$21,688
2021	2018	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Oral Diseases and Disorders Research	000	12	5/21/2021	NON-COMPETING CONTINUATION	-$21,688
														Subtotal = $511,465

Issue Date FY: 2020 ( Subtotal = $511,465 )
2020	2020	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Oral Diseases and Disorders Research	000	13	7/22/2020	COMPETING CONTINUATION	$511,465
														Subtotal = $511,465

Issue Date FY: 2018 ( Subtotal = $367,500 )
2018	2018	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Oral Diseases and Disorders Research	000	12	5/15/2018	NON-COMPETING CONTINUATION	$367,500
														Subtotal = $367,500

Issue Date FY: 2017 ( Subtotal = $367,500 )
2017	2017	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Oral Diseases and Disorders Research	000	11	5/22/2017	NON-COMPETING CONTINUATION	$367,500
														Subtotal = $367,500

Issue Date FY: 2016 ( Subtotal = $367,500 )
2016	2016	UNIVERSITY OF ALABAMA AT BIRMINGHAM	1530 3rd Avenue South, AB 1170	BIRMINGHAM	AL	35294	JEFFERSON	USA	Oral Diseases and Disorders Research	000	10	5/26/2016	NON-COMPETING CONTINUATION	$367,500
														Subtotal = $367,500

Issue Date FY: 2015 ( Subtotal = $367,500 )
2015	2015	UNIVERSITY OF ALABAMA AT BIRMINGHAM	1530 3rd Avenue South, AB 1170	BIRMINGHAM	AL	35294	JEFFERSON	USA	Oral Diseases and Disorders Research	002	9	8/19/2015	NON-COMPETING CONTINUATION	$367,500
2015	2014	UNIVERSITY OF CINCINNATI	PO BOX 210225	CINCINNATI	OH	45221	HAMILTON	USA	Oral Diseases and Disorders Research	001	7	2/5/2015	COMPETING CONTINUATION	-$315,758
2015	2014	UNIVERSITY OF ALABAMA AT BIRMINGHAM	1530 3rd Avenue South, AB 1170	BIRMINGHAM	AL	35294	JEFFERSON	USA	Oral Diseases and Disorders Research	000	8	2/5/2015	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$315,758
														Subtotal = $367,500

Issue Date FY: 2014 ( Subtotal = $381,625 )
2014	2014	UNIVERSITY OF CINCINNATI	PO BOX 210225	CINCINNATI	OH	45221	HAMILTON	USA	Oral Diseases and Disorders Research	000	7	7/7/2014	COMPETING CONTINUATION	$381,625
														Subtotal = $381,625

Issue Date FY: 2012 ( Subtotal = $373,148 )
2012	2012	UNIVERSITY OF CINCINNATI	PO BOX 210225	CINCINNATI	OH	45221	HAMILTON	USA	Oral Diseases and Disorders Research	000	6	7/31/2012	NON-COMPETING CONTINUATION	$373,148
														Subtotal = $373,148

Issue Date FY: 2011 ( Subtotal = $365,611 )
2011	2011	UNIVERSITY OF CINCINNATI	PO BOX 210225	CINCINNATI	OH	45221	HAMILTON	USA	Oral Diseases and Disorders Research	000	5	7/11/2011	NON-COMPETING CONTINUATION	$365,611
														Subtotal = $365,611

Issue Date FY: 2010 ( Subtotal = $376,918 )
2010	2010	UNIVERSITY OF CINCINNATI	PO BOX 210225	CINCINNATI	OH	45221	HAMILTON	USA	Oral Diseases and Disorders Research	002	4	7/14/2010	NON-COMPETING CONTINUATION	$376,918
2010	2009	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Oral Diseases and Disorders Research	001	2	2/16/2010	NON-COMPETING CONTINUATION	-$355,263
2010	2009	UNIVERSITY OF CINCINNATI	PO BOX 210225	CINCINNATI	OH	45221	HAMILTON	USA	Oral Diseases and Disorders Research	000	3	2/16/2010	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$355,263
														Subtotal = $376,918

Issue Date FY: 2009 ( Subtotal = $355,263 )
2009	2009	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Oral Diseases and Disorders Research	000	2	7/23/2009	NON-COMPETING CONTINUATION	$355,263
														Subtotal = $355,263

Issue Date FY: 2008 ( Subtotal = $408,473 )
2008	2008	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Oral Diseases and Disorders Research	001	1	8/12/2008	SUPPLEMENT FOR EXPANSION	$53,210
2008	2008	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Oral Diseases and Disorders Research	000	1	8/11/2008	NEW	$355,263
														Subtotal = $408,473

Grand Total All Awards = $6,273,022

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Mechanism of Nociception Induced by Innocuous Cold in Trigeminal System

Award Number: R01DE018661

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/11/2008

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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