Central glutamate signaling in postoperative pain regulation

项目摘要 术后疼痛是主要的发病率，术后持续使用阿片类药物导致了流行病。 对大脑内疼痛如何调节的机制理解的提高可以导致新的非阿片类药物 镇痛药的研制这项建议的长期目标是了解中央调控， 术后疼痛本申请的目的是定义前边缘皮层（PL）的作用， 前扣带皮层（anterior cingulate cortex，ACC）是啮齿类动物前额叶皮层的两个重要组成部分，在急性脑电活动的调节中起重要作用 和慢性术后疼痛。PL与人类背外侧前额叶皮层同源，已知其 经历慢性疼痛的突触变化，ACC是一个很好的描述区域，用于处理情感 不同物种的疼痛成分。我们的中心假设是，PL中神经活动的不平衡， ACC有助于术后疼痛症状，因此形成治疗靶点。我们的假设是 目前的文献支持，表明PL具有疼痛抑制作用，而ACC增强 疼痛厌恶，慢性疼痛导致ACC兴奋性增加和PL兴奋性降低。它 我们最近的结果也支持了这一点，这些结果表明，AMPAkines和氯胺酮，这些改变谷氨酸的药物， 信号和形状皮层电路，减少疼痛。在目标1中，我们将检验ACC失衡的假设， PL活动参与清醒自由行为大鼠的术后疼痛。我们将使用爪切口（PI） 模拟急性可逆性切口疼痛，并保留神经损伤（SNI）模拟术中后慢性疼痛 神经损伤我们首先将不平衡的前额叶活动与疼痛联系起来，通过显示同时发生的 疼痛行为持续时，PL的伤害性反应和ACC的反应增益，以及 这种神经变化，如疼痛解决，使用同时在体内细胞外记录的PL和ACC。 此外，为了测试这种不平衡对疼痛的因果影响，我们将表明光遗传PL激活，或ACC 抑制，逆转术后疼痛行为。接下来，我们将使用光电记录来解剖局部疼痛- 此外，我们将使用无偏的监督机器学习分析 验证PL和ACC活性失衡与术后慢性化的关系， 痛苦在目标2中，我们将测试药理学和电神经调节可以靶向 术后疼痛状态下PL/ACC活性失衡。我们会证明AMPAKINES和氯胺酮 增加PL输出并减少ACC活性以抑制疼痛并优化用于以下的时间和给药方案： 这些药物并测试治疗协同作用。我们还将优化侵入性和非侵入性电刺激 治疗疼痛的方案这个项目是创新的，因为它应用了一种新的系统神经科学 采用尖端技术来揭示中枢疼痛调节机制。这项工作意义重大 因为它产生了FDA批准的药物（氯胺酮和APMA因子）的新应用， 疼痛和新的深部脑或经颅刺激方法来治疗疼痛的蓝图。

PROJECT SUMMARY Postoperative pain is a major morbidity, and persistent opioid use after surgery has contributed to an epidemic. An improved mechanistic understanding of how pain is regulated within the brain can lead to novel non-opioid analgesic development. The long-term goal of this proposal is to understand the central regulation of postoperative pain. The objective of the current application is to define the role of prelimbic cortex (PL) and anterior cingulate cortex(ACC), two key components of the prefrontal cortexin rodents, in the regulation of acute and chronic postoperative pain. The PL is homologous to human dorsolateral prefrontal cortex that is known to undergo synaptic changes with chronic pain, and the ACC is a well-described region for processing affective component of pain across species. Our central hypothesis is that an imbalance in neural activities in the PL and ACC contributes to symptoms of postoperative pain and thus forms a therapeutic target. Our hypothesis is supported by the current literature showing that the PL has a pain-inhibitory role, whereas the ACC enhances pain aversion, and that chronic pain causes increased excitability in the ACC and hypo-excitability in the PL. It is also supported by our recent results demonstrating that AMPAkines and ketamine, drugs that alter glutamate signaling and shape cortical circuits, reduce pain. In Aim 1, we will test the hypothesis that an imbalance in ACC and PL activities contributes to postoperative pain in awake freely behaving rats. We will use paw incision (PI) to mimic acute reversible incisional pain, and spared nerve injury (SNI) to model chronic pain after intraoperative nerve damage. We will first correlate imbalanced prefrontal activities with pain, by showing a concurrent loss of nociceptive response in the PL and gain of response in the ACC as pain behavior persists, and the resolution of such neural changes as pain resolves, using simultaneous in vivo extracellular recordings of the PL and ACC. Further, to test the causal effect of this imbalance on pain, we will show that optogenetic PL activation, or ACC inhibition, reverses postoperative pain behaviors. Next, we will use optrode recordings to dissect a local pain- regulatory circuit fromthe PL to the ACC. Further, we will use an unbiased supervised machine learning analysis to validate the relationship between the imbalance in PL and ACC activities and the chronicity of postoperative pain. In Aim 2, We will test the hypothesis that pharmacologic and electrical neuromodulation can target imbalanced PL/ACC activities in the postoperative pain state. We will show that AMPAkines and ketamine increase PL outputs and reduce ACC activities to inhibit pain and optimize the timing and dosing regimens for these drugs and test therapeutic synergy. We will also optimize invasive and non-invasive electrical stimulation protocols in the PL to treat pain. This project is innovative because it applies a new systems neuroscience approach with cutting-edge techniques to uncover a central pain-regulatory mechanism. The work is significant because it produces novel applications of FDA-approved drugs (ketamine and APMAkines) for postoperative pain and a blueprint for new deep brain or transcranial stimulation methods to treat pain.