Central glutamate signaling in postoperative pain regulation - Revision - 1

术后疼痛调节中的中枢谷氨酸信号传导 - 修订版 - 1

• 批准号: 9707441
• 负责人: Jing Wang
• 金额: $ 9.9万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9707441
• 关键词: Acute; Administrative Supplement; Affective Symptoms; Analgesics; Anatomy; Anesthesiology; Applications Grants; Area; Behavior; Brain; Cells; Chronic; Clinical Trials; Collaborations; Data; Development; Dopamine Receptor; Electrophysiology (science); Enhancers; Ensure; Genetic Markers; Glutamates; Goals; Grant; Hypercapnic respiratory failure; Image; Interneurons; Label; Lead; Mission; Modeling; Morbidity - disease rate; National Institute of General Medical Sciences; Neurons; Neurosciences; Nucleus Accumbens; Operative Surgical Procedures; Opioid; Output; Pain; Pathway interactions; Persistent pain; Pharmaceutical Preparations; Photons; Postoperative Pain; Postoperative Period; Prefrontal Cortex; Public Health; Regulation; Reporting; Research; Resolution; Rewards; Rodent; Rodent Model; Role; Sensory; Specificity; Surgical incisions; System; Techniques; Testing; The Sun; United States National Institutes of Health; Work; Yang; awake; base; cell type; central pain; excitatory neuron; experience; experimental study; glutamatergic signaling; hippocampal pyramidal neuron; imaging system; in vivo; in vivo imaging; in vivo imaging system; inhibitory neuron; innovation; nerve injury; neural circuit; neuroregulation; novel; optogenetics; pain inhibition; pain model; pain symptom; parent grant; receptor; respiratory; spared nerve; success; temporal measurement

Postoperative pain is a major morbidity of surgery. The development of novel analgesics is hindered, however, by a fundamental gap in understanding how pain is regulated in the brain. The long-term goal of this proposal is to understand the central regulation of postoperative pain. The overall objective of this application is to define the role of glutamate signaling in the projection from the prefrontal cortex (PFC) to the nucleus accumbens (NAc) for the regulation of acute and chronic postoperative pain. The central hypothesis is that glutamate inputs from excitatory neurons in the PFC to the D1-type neurons in the NAc decreases pain and that AMPAkines can enhance glutamate signaling in this projection to treat postoperative pain. This hypothesis is supported by preliminary data showing that optogenetic activation of the PFC-NAc circuit inhibits persistent pain, and that systemic and intra-NAc or intra-PFC delivery of AMPAkines relieves chronic postoperative pain. It is further supported by our recent findings that PFC excitatory neurons are activated by pain. In Aim 1, the analgesic effect of the glutamate projection from the PFC to the NAc will be defined in two rodent models: the paw incision model for acute postoperative pain and the spared nerve injury model for persistent postoperative pain. We will image excitatory and inhibitory neurons in the PFC in these pain models. We will also examine the impact of AMPAkine analgesic treatment on distinct types of PFC neurons. In Aim 2, we will optogenetically activate the PFC and image D1- vs D2-type neurons in the NAc to examine which class of neurons are activated by this glutamatergic analgesic projection. We will also study the impact of AMPAkine treatment on these NAc neurons. This project is innovative because it applies a new systems neuroscience approach to uncover a novel central pain- inhibitory mechanism. The work is significant because it identifies the PFC-NAc pain-inhibitory circuit as a potential target for neuromodulation therapies and, more importantly, it establishes AMPAkines as postoperative drugs that can treat both sensory and affective symptoms of pain while opposing opioid-induced hypoventilation, laying the groundwork for clinical trials.

术后疼痛是手术的主要发病率。新颖的镇痛药的发展是 然而，由于理解大脑中疼痛的调节方式，阻碍了根本的差距。 该提议的长期目标是了解术后的中心监管 疼痛。该应用的总体目的是定义谷氨酸信号传导的作用 前额叶皮层（PFC）投射到伏隔核（NAC）的投影 调节急性和慢性术后疼痛。中心假设是谷氨酸 从PFC中的兴奋性神经元到NAC中D1型神经元的输入减轻疼痛 并且截肢可以在此投影中增强谷氨酸信号传导以治疗 术后疼痛。初步数据证明了这一假设 PFC-NAC电路的激活抑制了持续性疼痛，并且是全身和NAC内或内部或 Ampakines的PFC内递送可缓解慢性术后疼痛。进一步 在我们最近的发现的支持下，PFC兴奋性神经元被激活 疼痛。在AIM 1中，谷氨酸投射从PFC到NAC的镇痛作用 将在两个啮齿动物模型中定义：急性术后疼痛和 持续的术后疼痛的神经损伤模型。我们将图像兴奋性和 这些疼痛模型中PFC中的抑制性神经元。我们还将研究 对不同类型的PFC神经元的Ampakine镇痛治疗。在AIM 2中，我们将 通过光遗传学激活NAC中的PFC和Image D1-D2型神经元以检查 这种谷氨酸能镇痛投影激活了哪种类型的神经元。我们也会 研究氨后治疗对这些NAC神经元的影响。这个项目是创新的 因为它采用了一种新的系统神经科学方法来发现一种新型的中心疼痛 - 抑制机制。这项工作很重要，因为它可以识别PFC-NAC抑制性抑制作用 电路是神经调节疗法的潜在目标，更重要的是，它建立了 授权术作为术后药物，可以治疗疼痛的感觉和情感症状 同时反对阿片类药物引起的不足衰减，为临床试验奠定了基础。