Actions of Local Anesthetics on NMDA Receptors

描述（由申请人提供）：慢性疼痛是一种神经系统疾病状态的表现，表现为脊髓背角神经元兴奋性增加，称为中枢致敏。NMDA受体在中枢致敏的发展和维持中起关键作用。最近的证据支持局麻药对NMDA受体的抑制作用，然而，关于这种抑制发生的机制知之甚少。本项目将对临床上广泛使用的布比卡因和利多卡因两种酰胺局麻药抑制NMDA受体电流的机制进行研究。目的1将确定重组受体的剂量-反应关系，重点关注背角神经元中表达的主要亚型。目的2将通过单通道记录、动力学建模和计算刺激来研究抑制机制。目的3将探讨结构域决定因素涉及对麻醉剂的敏感性，以及这些如何转化局部麻醉剂的抑制机制。这个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来治疗和预防慢性疼痛。

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.