Central glutamate signaling in postoperative pain regulation

项目总结 术后疼痛是一种主要的发病率，术后持续使用阿片类药物导致了一种流行病。 对疼痛在大脑中如何调节的机械理解的改进可以导致新的非阿片类药物 止痛药的发展。这项提案的长期目标是理解中央对 术后疼痛。目前应用的目的是定义前脑皮质(PL)和 前扣带回(ACC)是啮齿动物前额叶皮质的两个重要组成部分，在调节急性脑损伤中起重要作用。 和慢性术后疼痛。PL与人类背外侧前额叶皮质同源，已知 伴随着慢性疼痛经历突触变化，而ACC是一个很好地描述的处理情感的区域 跨物种痛苦的组成部分。我们的中心假设是前额叶和前额叶的神经活动失衡 ACC会导致术后疼痛症状，从而形成治疗靶点。我们的假设是 目前的文献表明，PL具有止痛作用，而ACC则增强 疼痛厌恶，慢性疼痛导致ACC的兴奋性增加，PL的兴奋性降低。它 我们最近的研究结果也支持这一点，即安帕金斯和氯胺酮，这两种改变谷氨酸的药物 发出信号并塑造皮质回路，减轻疼痛。在目标1中，我们将测试Acc不平衡的假设 PL活性参与清醒自由行为大鼠术后疼痛的发生。我们将使用爪状切开术(PI) 模拟急性可逆性切口痛，避免神经损伤(SNI)造模术中慢性疼痛 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，通过显示同时失去 当疼痛行为持续存在时，PL中的伤害性反应和ACC中的反应获得，以及 使用体内同时记录的PL和ACC的细胞外记录，可以缓解疼痛等神经变化。 此外，为了测试这种失衡对疼痛的因果效应，我们将展示光遗传PL激活，或ACC 抑制，逆转术后疼痛行为。接下来，我们将使用光学电极记录来解剖局部疼痛- 从PL到ACC的调节电路。此外，我们将使用无偏监督的机器学习分析 验证PL和ACC活性失衡与术后慢性化的关系 疼痛。在目标2中，我们将测试药物和电神经调节可以靶向的假设 术后疼痛状态下PL/ACC活性失衡。我们将展示安帕金斯和氯胺酮 增加PL产量和降低ACC活性以抑制疼痛并优化时间和剂量方案 并测试这些药物的治疗协同作用.我们还将优化有创和无创电刺激 PL中治疗疼痛的方案。这个项目具有创新性，因为它应用了一种新的系统神经科学。 使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批准的术后药物(氯胺酮和APMAkines)的新应用 以及治疗疼痛的新的脑深部刺激或经颅刺激方法的蓝图。

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.