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.

项目总结