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Targeting Tiam1-mediated synaptic plasticity for the relief of opioid tolerance

Award Number: R01DA056673
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2023
PERIOD OF PERFORMANCE END DATE: 07/31/2027

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Targeting Tiam1-mediated synaptic plasticity for the relief of opioid tolerance - PROJECT SUMMARY/ABSTRACT The major objective of this proposal is to identify Tiam1-mediated synaptic plasticity as the molecular mechanism underlying opioid tolerance and validate Tiam1 as a promising therapeutic target in the relief of tolerance. Opioid pain medications remain the gold standard for the treatment of moderate to severe perioperative and chronic pain. However, over time, opioid use can result in tolerance, which is a primary driver for opioid misuse and overdose that directly contribute to increased morbidity and mortality. Opioid action at µ opioid receptors (MORs) expressed by nociceptors not only acutely depresses nociceptive transmission, but can induce glutamate release and brain-derived neurotrophic factor (BDNF) release in the spinal dorsal horn, which initiate downstream events that trigger the molecular, synaptic, and network-level adaptations that drive tolerance. Among these, synaptic plasticity is assumed to be the key determinant in opioid tolerance. However, the molecular mechanisms that trigger synaptic plasticity remain unclear. Rho GTPases, activated by guanine nucleotide exchange factors (GEFs) and inhibited by GTPase-activating proteins (GAPs), play important roles in dendritic spine morphogenesis and synaptic plasticity by controlling actin cytoskeleton remodeling in response to extracellular cues. We and others previously identified the Rac1-GEF Tiam1 as a critical regulator of dendrite, spine, and synapse development, which couples synaptic N-methyl-D-aspartate receptors (NMDARs) and TrkB receptors to Rac1 signaling-mediated actin cytoskeleton remodeling during brain development. In preliminary studies, we found that Tiam1 is activated in the spinal dorsal horn in response to chronic morphine treatment and it modulates synaptic remodeling by promoting chronic morphine-induced actin polymerization and synaptic NMDAR expression. Genetic deletion of Tiam1, deletion of Tiam1 from spinal dorsal horn neurons, or pharmacological blockade of Tiam1 signaling prevents the development of morphine tolerance. Moreover, combination morphine and Tiam1 inhibitor therapy reduce morphine tolerance in completer Freund’s adjuvant (CFA) inflammatory pain management. In this proposal, we will use a multidisciplinary approach to test our central hypothesis that Tiam1 links opioid-induced activation of synaptic NMDARs and/or TrkB receptors to Rac1 signaling in spinal dorsal horn neurons, resulting in synaptic structural and functional plasticity via actin cytoskeleton reorganization and NMDAR stabilization, which together underlies opioid tolerance. Moreover, we will determine whether blocking Tiam1-mediated synaptic plasticity with Tiam1 inhibitor or antisense oligonucleotides (ASOs) produces the long- lasting relief of opioid tolerance. The contribution of this proposed research is significant because it will uncover a previously unknown mechanism that underlies opioid tolerance and will provide a promising therapeutic target for the long-lasting relief of opioid tolerance.


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 = $454,197 )
2026	2026	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Drug Use and Addiction Research Programs	001	4	7/31/2026	NON-COMPETING CONTINUATION	$454,197
2026	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Drug Use and Addiction Research Programs	000	2	2/17/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $454,197

Issue Date FY: 2025 ( Subtotal = $456,126 )
2025	2025	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Drug Use and Addiction Research Programs	000	3	8/29/2025	EXTENSION WITH OR WITHOUT FUNDS	$456,126
														Subtotal = $456,126

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Drug Use and Addiction Research Programs	000	1	4/28/2024	NEW	-$1,670
2024	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Drug Use and Addiction Research Programs	001	2	4/28/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$1,670
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = -$341,739 )
2023	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Drug Use and Addiction Research Programs	001	2	6/9/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$1,486,264
2023	2022	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Drug Use and Addiction Research Programs	000	1	6/8/2023	NEW	-$1,828,003
														Subtotal = -$341,739

Issue Date FY: 2022 ( Subtotal = $1,835,048 )
2022	2022	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Drug Use and Addiction Research Programs	000	1	8/10/2022	NEW	$1,835,048
														Subtotal = $1,835,048

Grand Total All Awards = $2,403,632

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Targeting Tiam1-mediated synaptic plasticity for the relief of opioid tolerance

Award Number: R01DA056673

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2023

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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