Central glutamate signaling in postoperative pain regulation - Revision - 1

术后疼痛是外科手术的主要并发症之一。新型镇痛药的发展是 然而，在理解疼痛如何在大脑中调节方面存在根本性的差距。 这项建议的长期目标是了解手术后的中枢调节 痛苦本申请的总体目标是定义谷氨酸信号传导在以下中的作用： 前额叶皮层（PFC）到丘脑核（NAc）的投射， 急性和慢性术后疼痛的调节。核心假设是谷氨酸 从PFC中的兴奋性神经元到NAc中的D1型神经元的输入减少疼痛 AMPakines可以增强谷氨酸信号传导， 术后疼痛这一假设得到了初步数据的支持，这些数据表明， PFC-NAc回路的激活抑制持续性疼痛，并且全身和NAc内或 AMPakine的PFC内递送减轻慢性术后疼痛。进一步 我们最近的发现支持了这一点，即PFC兴奋性神经元被激活， 痛苦目的1：观察PFC向NAc的谷氨酸投射的镇痛作用 将在两种啮齿动物模型中定义：急性术后疼痛的爪切口模型和 保留神经损伤模型用于持续性术后疼痛。我们会想象兴奋， 在这些疼痛模型中PFC中的抑制性神经元。我们亦会研究 AMPakine对不同类型PFC神经元的镇痛治疗。在目标2中，我们 光遗传学激活PFC并成像NAc中的D1- vs D2-型神经元以检查 哪类神经元被这种镇痛投射激活。我们还将 研究AMPakine治疗对这些NAc神经元的影响。这个项目是创新的 因为它应用了一种新的系统神经科学方法来揭示一种新的中枢疼痛- 抑制机制这项工作是重要的，因为它确定了PFC-NAc疼痛抑制 电路作为神经调节疗法的潜在靶点，更重要的是，它建立了 AMPakines作为术后药物，可治疗疼痛的感觉和情感症状 同时反对阿片类药物引起的换气不足，为临床试验奠定了基础。

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.