Stress-induced descending facilitation from amygdala kappa opioid receptors in functional pain

功能性疼痛中杏仁核卡帕阿片受体的压力诱导的下行促进

基本信息

批准号：
9896878
负责人：
Volker Neugebauer
金额：
$ 54.16万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9896878
关键词：
Acute Address Affect Affective Agonist Amygdaloid structure Animals Area Behavioral Behavioral Assay Brain Cell Nucleus Chronic Chronic Fatigue Syndrome Clinical Clinical Trials Data Development Disinhibition Dynorphins Electrophysiology (science)Emotional Exposure to Fibromyalgia Frequencies Future Genetic Goals Gulf War Headache Health Human Hyperalgesia Immunohistochemistry Injury Interruption Interstitial Cystitis Investigation Irritable Bowel Syndrome Knowledge Lead Link Mediating Memory Methods Migraine Modeling Molecular Molecular Target Morphine Mus Neuronal Plasticity Neurons Nociception Opioid Opioid Antagonist Output Pain Pain Disorder Pain Research Pain intensity Pain quality Pain-Free Patients Peripheral Pharmaceutical Preparations Physiology Predisposing Factor Receptor Signaling Resolution Rodent Model Sensory Signal Transduction Slice Stimulus Stress Structure Synapses Syndrome System Tactile Hyperalgesias Temporomandibular Joint Disorders Testing Therapeutic Therapeutic Intervention Thermal Hyperalgesias Time United States National Institutes of Health Vulvodynia Work allodynia base behavioral response biological adaptation to stress cell type central sensitization chronic pain clinically relevant dorsal horn dynorphin receptor experience experimental study innovation insight interdisciplinary approach kappa opioid receptors neural circuit neurobiological mechanism norbinaltorphimine novel novel therapeutics optogenetics pain behavior pain patient pain reduction pre-clinical prevent resilience response stressor targeted treatment tissue injury

项目摘要

Project Summary Many patients suffer from chronic pain in the absence of identifiable injury. Such pains are termed “functional” and include irritable bowel syndrome, temporomandibular joint disorder, fibromyalgia, migraine and others. Functional pain patients experience pain free periods that are interrupted by attacks of pain that can persist for variable periods of time. The chronification of these pain disorders has been linked to the number and frequency of attacks suggesting that repeated nociceptive episodes promote and maintain a state of central sensitization that reflects increased vulnerability to future attacks. Functional pain patients commonly identify stress as a key trigger of pain episodes but neurobiological mechanisms remain to be determined. In this project, we test the novel hypothesis that in sensitized states, stress-induced kappa opioid receptor (KOR) signaling in the amygdala promotes functional pain responses. We have developed an injury-free rodent model of stress-related functional pain based on hyperalgesic priming with opioids. Opioids have been shown to produce opioid-induced hyperalgesia (OIH) in humans and in animals. OIH is characterized by generalized tactile and thermal hyperalgesia, decreased nociceptive thresholds, increase temporal summation, and a loss of descending noxious inhibitory controls (DNIC). Following resolution of OIH, and in the absence of stress, animals have normal pain responses. Hyperalgesic priming, however, produces a state of latent sensitization so that animals previously exposed to morphine are now prone to stress-induced hyperalgesia and a loss of DNIC that is prevented by blockade of KOR signaling within the central nucleus of the amygdala (CeA). Our electrophysiological data support a KOR-mediated disinhibition of CeA neurons that promote pain. We will use advanced behavioral and electrophysiological approaches with optogenetic and chemogenetic methods to demonstrate that activation of CeA KOR neurons in control, unprimed mice promotes pain-related responses (Specific Aim 1). These studies will establish the neural circuitry within the amygdala that may underlie a novel KOR-mediated pronociceptive CeA output that is engaged through disinhibition. Specific Aim 2 will determine if exogenous activation of the CeA KOR circuit results in amplified pain responses following priming- induced latent sensitization. In Specific Aim 3 we will determine whether blockade of stress-induced endogenous CeA KOR signaling reduces pain responses following priming-induced latent sensitization. The proposed studies will characterize a previously unknown stress-related KOR mediated hyperalgesic circuit from CeA and determine how this circuit may promote decreased resilience to stress. Importantly, these studies may unravel mechanisms for therapeutic interventions in stress-related functional pain disorders through an actionable molecular target. KOR antagonists are currently in development.

项目概要许多患者在没有明显损伤的情况下患有慢性疼痛，这种疼痛被称为“功能性”疼痛。包括肠易激综合症、颞下颌关节紊乱、纤维肌痛、偏头痛等。功能性疼痛患者会经历无痛期，但会被持续持续很长时间的疼痛发作打断。这些疼痛疾病的慢性化与数量和频率有关。攻击表明反复的伤害性发作促进并维持中枢敏化状态功能性疼痛患者通常认为压力是一个关键因素。疼痛发作的触发因素，但神经生物学机制仍有待确定。在这个项目中，我们测试了一个新的假设，即在敏化状态下，压力诱导的 kappa 阿片受体 (KOR) 杏仁核中的信号传导促进功能性疼痛反应我们开发了一种无损伤的啮齿动物模型。已证明基于阿片类药物的痛觉过敏可以减轻与压力相关的功能性疼痛。在人类和动物中产生阿片类药物引起的痛觉过敏 (OIH)，OIH 的特点是普遍性。触觉和热痛觉过敏、伤害性阈值降低、时间总和增加以及感觉丧失 OIH 消退后，在没有应激的情况下，动物进行下降性毒性抑制控制 (DNIC)。具有正常的疼痛反应，然而，痛觉过敏引发会产生潜在的敏化状态，因此以前接触过吗啡的动物现在容易出现应激引起的痛觉过敏和 DNIC 丧失，这是通过阻断杏仁核中央核 (CeA) 内的 KOR 信号传导来阻止的。电生理学数据支持 KOR 介导的 CeA 神经元去抑制，从而促进疼痛。我们将使用先进的行为和电生理学方法以及光遗传学和化学遗传学方法方法证明在对照、未启动的小鼠中 CeA KOR 神经元的激活会促进疼痛相关这些研究将建立杏仁核内可能存在的神经回路。一种新颖的 KOR 介导的伤害性 CeA 输出通过特定目标 2 参与。确定 CeA KOR 回路的外源激活是否会导致启动后疼痛反应放大在特定目标 3 中，我们将确定是否阻断应激诱导的内源性致敏。 CeA KOR 信号传导可减少启动诱导的潜在敏化后的疼痛反应。拟议的研究将描述以前未知的与压力相关的 KOR 介导的痛觉过敏回路重要的是，这些研究表明该回路如何降低抗压能力。可能通过以下方式揭示压力相关功能性疼痛障碍的治疗干预机制目前正在开发可操作的分子靶点。