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

靶向 Tiam1 介导的突触可塑性以缓解阿片类药物耐受

• 批准号: 10800301
• 负责人: Lingyong Li
• 金额: $ 148.63万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10800301
• 关键词: Targeting; Tiam1; mediated; synaptic; plasticity

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.

项目摘要/摘要 该提案的主要目的是将TIAM1介导的合成可塑性确定为分子机制 基本的阿片类药物耐受性和验证TIAM1作为耐受性的有前途的治疗靶标。 止痛药仍然是治疗中度至重度时期和慢性的金标准 疼痛。但是，随着时间的流逝，阿片类药物的使用可能会导致耐受性，这是阿片类Missuse和 过量服用直接导致发病率和死亡率的增加。 µ阿片类药物接收器（MOR）的阿片类药物作用 伤害感受器表达不仅急性降低伤害感受器的传播，还可以诱导谷氨酸释放 在脊柱背角中释放的脑衍生的神经营养因子（BDNF）释放，启动下游事件 这会触发驱动公差的分子，突触和网络级适应。其中，突触 假定可塑性是阿片类药物耐受性的关键决定剂。但是，分子机制 触发合成可塑性尚不清楚。 Rho GTPases，被鸟嘌呤核丁基交换因子激活 （GEF）并被GTPase激活蛋白（GAP）抑制，在树突状脊柱中起重要作用 通过控制肌动蛋白细胞骨架重塑，对细胞外的重塑，形态发生和突触可塑性 提示。我们和其他人以前以前将Rac1-GEF TIAM1确定为树突，脊柱和 突触发育，伴侣突触N-甲基-D-天冬氨酸受体（NMDARS）和TRKB受体 到Rac1信号介导的肌动蛋白细胞骨架重塑过程中。在初步研究中，我们 发现tiam1在响应慢性吗啡治疗的情况下在脊柱背角中激活并调节 突触重塑，通过促进慢性吗啡诱导的肌动蛋白聚合和突触NMDAR 表达。 TIAM1的遗传缺失，脊柱背角神经元的TIAM1缺失或药物 TIAM1信号传导的封锁阻止了吗啡耐受性的发展。而且，组合吗啡 TIAM1抑制剂疗法降低了完全弗朗德（CFA）炎症性疼痛中的吗啡耐受性 管理。在此提案中，我们将使用多学科的方法来检验我们的中心假设，即TIAM1 将阿片类药物诱导的突触NMDAR和/或TRKB受体的激活与脊柱背侧的Rac1信号传导联系起来 角神经元，通过肌动蛋白细胞骨架重组和 NMDAR稳定，这是阿片类药物耐受性的基础。而且，我们将确定是否阻止 TiAM1介导的Tiam1抑制剂或反义寡核苷酸（ASO）的突触可塑性可产生长期 阿片类药物耐受性的持久缓解。这项拟议研究的贡献很重要，因为它将发现 以前未知的机制，其基础是阿片类药物耐受性，并将提供有希望的治疗靶标 为了持续的阿片类药物耐受性。