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并发症。新型镇痛药的开发 然而，对于大脑如何调节疼痛的理解存在根本性的差距，这阻碍了这一研究。 该提案的长期目标是了解术后的中枢调节 疼痛。该应用的总体目标是定义谷氨酸信号传导在 从前额皮质 (PFC) 到伏隔核 (NAc) 的投影 急性和慢性术后疼痛的调节。中心假设是谷氨酸 从 PFC 中的兴奋性神经元到 NAc 中的 D1 型神经元的输入可减轻疼痛 AMPAkines 可以增强此投射中的谷氨酸信号传导以治疗 术后疼痛。这一假设得到了初步数据的支持，表明光遗传学 PFC-NAc 回路的激活可抑制持续性疼痛，并且全身性和 NAc 内或 PFC 内输送 AMPAkins 可缓解慢性术后疼痛。更是进一步 我们最近的发现支持了 PFC 兴奋性神经元的激活 疼痛。在目标 1 中，从 PFC 到 NAc 的谷氨酸投射的镇痛作用 将定义两种啮齿动物模型：用于急性术后疼痛的爪切口模型和 用于术后持续疼痛的备用神经损伤模型。我们将想象令人兴奋和 在这些疼痛模型中，PFC 中的抑制性神经元。我们还将研究影响 AMPAkine 对不同类型的 PFC 神经元进行镇痛治疗。在目标 2 中，我们将 光遗传学激活 PFC 并对 NAc 中的 D1 型与 D2 型神经元进行成像以进行检查 哪一类神经元被谷氨酸能镇痛投射激活。我们也会 研究 AMPAkine 治疗对这些 NAc 神经元的影响。这个项目很创新 因为它应用了一种新的系统神经科学方法来发现一种新的中枢疼痛—— 抑制机制。这项工作意义重大，因为它确定了 PFC-NAc 的镇痛作用 电路作为神经调节疗法的潜在目标，更重要的是，它建立了 AMPAkines 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通气不足，为临床试验奠定基础。