Actions of Local Anesthetics on NMDA Receptors

描述（由申请人提供）：慢性疼痛是一种神经疾病状态的表现，表现为脊髓背角神经元兴奋性增加，称为中枢致敏。NMDA受体在中枢敏感化的发展和维持中起关键作用。最近的证据支持局部麻醉剂对NMDA受体的抑制作用，然而，很少有人知道这种抑制发生的机制。本课题旨在探讨临床上广泛应用的两种酰胺类局麻药布比卡因和利多卡因抑制NMDA受体电流的机制。目的1将确定重组受体的剂量-反应关系，重点是在背角神经元中表达的主要亚型。目的二是利用单通道记录、动力学模拟和计算机模拟技术研究抑制机制。目的3将探讨麻醉药敏感性的结构域决定因素，以及这些决定因素如何解释局麻药的抑制机制。本项目的结果将增加对预防或改善中枢致敏的药理学策略的理解，并可能通过使用局部麻醉剂治疗和预防慢性疼痛。 公共卫生相关性：在美国，慢性疼痛是残疾的主要原因，其由背角中的被称为中枢敏化的兴奋性通路的不良适应性NMDA受体介导引起。NMDA受体阻滞剂抑制动物模型中的疼痛超敏反应症状。本申请将研究两种广泛使用的局部麻醉剂利多卡因和布比卡因降低NMDA受体活性的机制，并将提供有关局部麻醉如何预防或减少中枢致敏的发展所需的信息。

DESCRIPTION (provided by applicant): Chronic pain is the expression of a neurological disease state that manifests as increased excitability of dorsal horn neurons in the spinal cord known as central sensitization. NMDA receptors play a pivotal role in development and maintenance of central sensitization. Recent evidence supports an inhibitory effect of local anesthetics on NMDA receptors, however, little is known as to the mechanism by which this inhibition occurs. This project will evaluate the mechanism by which bupivacaine and lidocaine, two amide local anesthetics widely used in clinical practice inhibit NMDA receptor currents. Aim 1 will determine dose-response relationships in recombinant receptors focusing on the main isoforms expressed in dorsal horn neurons. Aim 2 will investigate the mechanism of inhibition with single-channel recordings, kinetic modeling and computational stimulation. Aim 3 will explore the structural domain determinants involved in sensitivity to anesthetics, and how these translate local anesthetics' inhibitory mechanism. Results from this project will increase understanding of pharmacologic strategies to prevent or ameliorate central sensitization and possible treatment and prevention of chronic pain by using local anesthetics. PUBLIC HEALTH RELEVANCE: Chronic pain, a leading cause of disability in the United States, results from a mal-adaptive NMDA receptor- mediated of excitatory pathways in the dorsal horn known as central sensitization. NMDA receptor blockers suppress pain hypersensitivity symptoms in animal models. This application will investigate the mechanism by which lidocaine and bupivacaine, two widely used local anesthetics, reduce NMDA receptor activity and will provide needed information about how local anesthesia can prevent or reduce the development of central sensitization.