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：
10379964
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 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10379964
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 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 Persian Gulf Syndrome 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 chronification 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.

项目摘要在没有可识别损伤的情况下，许多患者患有慢性疼痛。这种痛苦被称为“功能” 包括肠易激综合征，颞下颌关节疾病，纤维肌痛，偏头痛等。功能性疼痛患者经历了无痛时期，被疼痛攻击中断，可以持续存在可变的时间。这些疼痛障碍的编年期已与数量和频率有关攻击表明重复的伤害感染发作会促进和维持中央灵敏度状态这反映了对未来攻击的脆弱性。功能性疼痛患者通常将压力识别为关键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，我们检验了一个新的假设，即在敏感状态下，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。我们已经开发了无损伤的啮齿动物模型基于阿片类药物的高温启动的应力相关功能疼痛。阿片类药物已被证明在人类和动物中产生了OioID诱导的痛觉过敏（OIH）。 OIH以广义为特征触觉和热痛觉过敏，伤害性阈值降低，临时总和增加以及损失下降有害抑制控制（DNIC）。在解决OIH之后，在没有压力的情况下，动物具有正常的疼痛反应。但是，高温启动会产生潜在灵敏度的状态以前暴露于吗啡的动物现在容易受到压力诱发的痛觉过敏，并且丧失了dnic的损失。在杏仁核（CEA）的中央核内阻断KOR信号传导阻碍。我们的电生理数据支持KOR介导的抑制CEA神经元的抑制，以促进疼痛。我们将使用光学遗传学和化学遗传学的先进的行为和电生理方法证明在对照中激活CEA KOR神经元的方法，未发生的小鼠促进与疼痛有关响应（特定目标1）。这些研究将在杏仁核内建立神经回路通过抑制作用参与的新型KOR介导的Procatipative CEA输出。具体目标2将确定CEA KOR回路的外源激活是否会导致启动后的放大疼痛反应诱导潜在的传感化。在特定目标3中，我们将确定是否阻塞应力引起的内源性 CEA KOR信号传导减少了引发引起的潜在传感化后的疼痛反应。拟议的研究将表征先前未知的应力相关的KOR介导的痛觉过敏电路从CEA确定该电路如何促进压力的弹性。重要的是，这些研究可能会通过通过一个可操作的分子靶标。 Kor Antoganist目前正在开发中。