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

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2022 · $1,486,264

## Abstract

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 t...

## Key facts

- **NIH application ID:** 10800301
- **Project number:** 7R01DA056673-02
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Lingyong Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,486,264
- **Award type:** 7
- **Project period:** 2023-04-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10800301

## Citation

> US National Institutes of Health, RePORTER application 10800301, Targeting Tiam1-mediated synaptic plasticity for the relief of opioid tolerance (7R01DA056673-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10800301. Licensed CC0.

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