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Central glutamate signaling in postoperative pain regulation - Renewal

术后疼痛调节中的中枢谷氨酸信号 - 更新

基本信息

批准号：
10664865
负责人：
Jing Wang
金额：
$ 46.99万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10664865
关键词：
Acids Acute Address Affective Analgesics Animals Anterior Behavior Brain Brain region Cephalic Chronic Data Development Dose Electric Stimulation Electrophysiology (science)Enhancers Epidemic FDA approved Funding Glutamates Goals Human Hyperactivity In Vitro Ketamine Literature Machine Learning Mental Depression Methods Modeling Modification Morbidity - disease rate N-Methyl-D-Aspartate Receptors Nervous System Neurons Neurosciences Operative Surgical Procedures Organism Output Pain Pain Clinics Pharmaceutical Preparations Physiological Physiology Postoperative Pain Postoperative Period Pre-Clinical Model Prefrontal Cortex Process Protocols documentation Publishing Rattus Regimen Regulation Research Resolution Rodent Rodent Model Role Sensory Shapes Signal Transduction Slice Surgical incisions Symptoms Synapses System Techniques Testing Therapeutic Work addiction allodynia antagonist awake central pain chronic pain cingulate cortex combat design extracellular glutamatergic signaling improved in vivo innovation nerve damage nerve injury neural neuropsychiatric disorder neuroregulation nociceptive response non-opioid analgesic novel novel therapeutics opioid epidemic opioid use optogenetics pain behavior pain inhibition pain model pain reduction pain relief pain symptom pharmacologic receptor response spared nerve supervised learning synergism therapeutic evaluation therapeutic target

项目摘要

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 cortex in 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.

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)和前扣带回皮质(ACC)是啮齿类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。

项目成果

期刊论文数量（40）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Deciphering neuronal population codes for acute thermal pain.

DOI：
10.1088/1741-2552/aa644d
发表时间：
2017-06
期刊：
Journal of neural engineering
影响因子：
4
作者：
Chen Z;Zhang Q;Tong APS;Manders TR;Wang J
通讯作者：
Wang J

Local field potential decoding of the onset and intensity of acute pain in rats.

DOI：
10.1038/s41598-018-26527-w
发表时间：
2018-05-29
期刊：
Scientific reports
影响因子：
4.6
作者：
Zhang Q;Xiao Z;Huang C;Hu S;Kulkarni P;Martinez E;Tong AP;Garg A;Zhou H;Chen Z;Wang J
通讯作者：
Wang J

Ketamine normalizes high-gamma power in the anterior cingulate cortex in a rat chronic pain model.