Molecular Determinants of Synaptic Plasticity in Chronic Pain

慢性疼痛突触可塑性的分子决定因素

• 批准号: 9752685
• 负责人: Shao-Rui Chen
• 金额: $ 42.73万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9752685
• 关键词: Acids; Behavioral; Binding; Cations; Chronic; Clinical; Coupling; Development; Diabetic Neuropathies; Epilepsy; Glutamate Receptor; Glutamates; Goals; In Vitro; Link; Mediating; Molecular; Nerve Pain; Neuraxis; Neuropathy; Nociception; Peptides; Permeability; Physiological; Play; Posterior Horn Cells; Presynaptic Terminals; Prevalence; Proteins; Research; Role; Spinal; Spinal Cord; Surface; Synapses; Synaptic Membranes; Synaptic Transmission; Synaptic plasticity; Testing; Therapeutic; Therapeutic Effect; biophysical properties; chronic neuropathic pain; chronic pain; dorsal horn; gabapentin; in vivo; insight; interdisciplinary approach; nerve injury; neurotransmitter release; novel; novel therapeutics; painful neuropathy; pregabalin; programs; protein complex; receptor; trafficking; transmission process; voltage; von Willebrand Factor

Project Summary The overall goal of our research program is to elucidate the underlying molecular principles that govern synaptic plasticity associated with chronic pain. Chronic neuropathic pain is a significant and unmet clinical problem. Glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) mediate the vast majority of fast excitatory synaptic transmission in the mammalian central nervous system. AMPARs are tetrameric cation channels composed of a combinational assembly of four subunits, GluA1 through GluA4. GluA2 is particularly important for the biophysical properties of AMPARs because GluA2-containing AMPARs are impermeable to Ca2+. In contrast, GluA2-lacking AMPARs show inward-rectifying currents and have a high Ca2+ permeability and are thus referred to as Ca2+-permeable AMPARs (CP-AMPARs). The prevalence of synaptic CP-AMPARs of spinal dorsal horn neurons is markedly increased in neuropathic pain. However, the molecular mechanisms underlying the switch of AMPAR subunit composition in neuropathic pain remain little known. The major objective of our proposal is to determine the key molecular mechanism responsible for regulating the assembly and trafficking of CP-AMPARs in neuropathic pain. α2δ-1, often considered a Ca2+ channel subunit, is upregulated in the spinal dorsal horn in neuropathic pain. Our preliminary studies showed that α2δ-1 interacted with AMPAR subunits in vitro and in vivo and that increased α2δ-1 expression promoted synaptic incorporation of CP-AMPARs in the spinal dorsal horn. In this proposal, we will test our overall hypothesis that α2δ-1 potentiates the synaptic CP-AMPAR prevalence in spinal dorsal horn neurons in neuropathic pain through physical interaction with AMPAR subunits to preferentially regulate their subunit composition and synaptic trafficking. We will use a multidisciplinary approach to study α2δ-1–AMPAR coupling and its distinct role in neuropathic pain at molecular, cellular, and behavioral levels. At the completion of our project, we will gain significant mechanistic insight into the poorly defined role of α2δ-1 in synaptic plasticity and neuropathic pain caused by nerve injury and diabetic neuropathy. This new information will redefine the physiological function α2δ-1 and the role of α2δ-1–bound CP-AMPARs in the therapeutic effects of gabapentinoids. Therefore, the findings from the proposed studies will have a sustained positive impact by advancing our understanding of the synaptic mechanism of neuropathic pain, leading to the development of new therapies for chronic neuropathic pain.

项目摘要 我们研究计划的总体目标是阐明控制突触的潜在分子原理， 与慢性疼痛相关的可塑性。慢性神经病理性疼痛是一个重要且尚未解决的临床问题。 谷氨酸α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPAR）介导绝大多数 在哺乳动物中枢神经系统中快速兴奋性突触传递。AMPAR是四聚阳离子 通道由四个亚基（GluA 1至GluA 4）的组合组装组成。GluA 2特别是 这对于AMPAR的生物物理性质很重要，因为含GluA 2的AMPAR对Ca 2+是不可渗透的。 相比之下，缺乏GluA 2的AMPAR显示内向整流电流，具有高Ca 2+渗透性， 因此称为Ca 2+可渗透的AMPAR（CP-AMPAR）。脊髓背角突触CP-AMPAR的患病率 神经性疼痛时背角神经元明显增加。然而，潜在的分子机制 神经病理性疼痛中AMPAR亚基组成转换仍知之甚少。我们的主要目标是 这项研究的目的是确定负责调节蛋白质组装和运输的关键分子机制。 CP-AMPAR在神经性疼痛中的应用α2δ-1通常被认为是一种钙通道亚单位，在脊髓中上调。 神经性疼痛的背角。我们的初步研究表明α2δ-1在体外与AMPAR亚基相互作用 α2δ-1表达的增加促进了脊髓中CP-AMPAR的突触掺入， 背角在这个提议中，我们将测试我们的总体假设，即α2δ-1增强突触CP-AMPAR 通过与AMPAR亚单位的物理相互作用在神经病理性疼痛中脊髓背角神经元的患病率 优先调节其亚基组成和突触运输。我们将采用多学科方法 从分子、细胞和行为学角度研究α2δ-1-AMPAR偶联及其在神经病理性疼痛中的作用 程度.在我们的项目完成时，我们将获得对定义不清的角色的重要的机械见解， α2δ-1在神经损伤和糖尿病神经病变引起的突触可塑性和神经病理性疼痛中的作用这个新 信息将重新定义生理功能α2δ-1和α2δ-1结合的CP-AMPAR在 加巴喷丁类化合物的治疗作用。因此，拟议研究的结果将具有持续的 通过推进我们对神经病理性疼痛的突触机制的理解， 开发慢性神经性疼痛的新疗法。