Kappa Opioid Receptor in Paraventricular Nucleus of Thalamus

丘脑室旁核中的 Kappa 阿片受体

基本信息

批准号：
10659960
负责人：
LEE-YUAN LIU-CHEN
金额：
$ 60.74万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-30 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10659960
关键词：
Abbreviations Absence of pain sensation Addictive Behavior Amygdaloid structure Analgesics Anterior Anti-Anxiety Agents Antidepressive Agents Antipruritic Effect Anxiety Area Arousal Behavior Brain Brain Stem Brain region California Cell Nucleus Chronic Collaborations Coping Behavior Coupled Diuresis Dorsal Drug Addiction Drug abuse Dynorphins Enterobacteria phage P1 Cre recombinase Exhibits Fright Homeostasis Human Hypothalamic structure In Situ Hybridization Injections Knock-in Mouse Knockout Mice Knowledge acquisition Limbic System Link Literature LoxP-flanked allele Mediating Mental Depression Mental Health Messenger RNA Midline Thalamic Nuclei Morphine Mus Mutant Strains Mice Naloxone Neuroanatomy Neurons Nucleus Accumbens Opioid Antagonist Opioid Receptor Opioid agonist Pathway interactions Pennsylvania Peptides Play Prefrontal Cortex Proteins Psychopathology Publishing Rabies Rabies virus Reporter Research Rewards Rodent Role Secure Seminal Services Source Stress Stress and Coping Structure Structure of paraventricular nucleus of thalamus Structure of terminal stria nuclei of preoptic region Tamoxifen Testing Time Universities Ventral Tegmental Area Viral Viral Vector Virus Visceral pain Water Withdrawal Work anxiety-like behavior base behavioral response biological adaptation to stress clinical development conditional knockout conditioned fear dysphoria experience genetic approach in vivo inducible Cre kappa opioid receptors negative affect nerve supply neuronal circuitry pain model receptor response side effect

项目摘要

The kappa opioid receptor (KOR) is one of the three opioid receptors. KOR agonists produce analgesic and anti-pruritic effects, but their development for clinical use has been limited by side effects, most importantly dysphoria and psychotomimesis. KOR antagonists display antidepressant- and anti-anxiety-like effects in rodents and may be useful for the treatment of drug addiction in humans. The paraventricular nucleus of the thalamus (PVT), the most dorsal nucleus of the thalamic midline nuclei, is among the brain regions that express high levels of KOR. The PVT receives inputs from the prelimbic, infralimbic and insular cortices, the ventral subiculum and many hypothalamic and brain stem nuclei. The PVT sends dense projections to several limbic structures including the amygdala, the bed nucleus of the stria terminalis, and the core and shell of the nucleus accumbens. The PVT is part of the brain anxiety network and is involved in stress responses, fear, anxiety, arousal, reward, and homeostasis. The KOR level in the PVT is similar to that in the ventral tegmental area, but KOR in the PVT has not yet been characterized. For the proposed studies, we have generated a mutant mouse line expressing tamoxifen-inducible Cre conjugated to KOR (KOR-iCre). In this application, we propose the following three specific aims. For the Aim 1, the origins of afferent projections to PVT KOR- expressing neurons will be determined by Cre-dependent rabies virus-mediated monosynaptic retrograde tracing. The brain regions of efferent projections of PVT KOR-expressing neurons will then be characterized using Cre-dependent anterograde tracing. Whether KOR+ neurons in the PVT projecting to different brain regions receive innervations from different brain areas will also be investigated. Finally, the origin of dynorphin inputs into the PVT will be explored. For the Aim 2, we will elucidate the functions of PVT KOR by examining the effects of conditional deletion of PVT KOR on behaviors such as KOR agonist-induced analgesia in a visceral pain model, conditioned place aversion, naloxone-precipitated withdrawal signs, aversion after chronic morphine and anxiety-like behaviors. For the Aim 3, we will examine the roles of PVT KOR-expressing neurons in stress-related behaviors, fear conditioning and aversion by activation and inhibition of these neurons via chemogenetic approaches. This will be the first time that these PVT KOR-expressing neurons and KOR per se are investigated in a comprehensive manner. Determining the neuronal circuitries in which the KOR is involved and the functional significance of KOR+ circuits will enhance our understanding of KOR functional neuroanatomy and KOR-mediated aversion, anxiety, stress responses and other psychopathology. The knowledge acquired may provide the neuronal basis for developing KOR antagonists as anti-anxiety agents.

kappa阿片受体（KOR）是三种阿片受体之一。 KOR 激动剂产生镇痛作用止痒作用，但其临床应用的开发受到副作用的限制，最重要的是烦躁不安和拟精神病。 KOR 拮抗剂在以下疾病中表现出抗抑郁和抗焦虑样作用啮齿类动物，可能可用于治疗人类的毒瘾。室旁核丘脑 (PVT) 是丘脑中线核团最背侧的核，是负责控制丘脑中线的大脑区域之一。表达高水平的 KOR。 PVT 接收来自前边缘、下边缘和岛叶皮质的输入，腹侧下托和许多下丘脑和脑干核团。 PVT 将密集的投影发送到多个边缘结构包括杏仁核、终纹床核以及杏仁核的核心和外壳伏隔核。 PVT 是大脑焦虑网络的一部分，与压力反应、恐惧、焦虑、觉醒、奖励和体内平衡。 PVT 中的 KOR 水平与腹侧被盖层中的 KOR 水平相似区，但 PVT 中的 KOR 尚未得到表征。对于拟议的研究，我们生成了表达与 KOR 缀合的他莫昔芬诱导型 Cre 的突变小鼠系 (KOR-iCre)。在这个应用程序中，我们提出以下三个具体目标。对于目标 1，PVT KOR 的传入投射的起源- 表达神经元将由 Cre 依赖性狂犬病病毒介导的单突触逆行决定追踪。然后将表征 PVT KOR 表达神经元传出投射的大脑区域使用依赖于 Cre 的顺行追踪。 PVT中的KOR+神经元是否投射到不同的大脑还将研究来自不同大脑区域的神经支配区域。最后，强啡肽的起源将探讨对 PVT 的投入。对于目标 2，我们将通过检查来阐明 PVT KOR 的功能有条件删除 PVT KOR 对 KOR 激动剂诱导的镇痛等行为的影响内脏痛模型、条件性位置厌恶、纳洛酮诱发的戒断症状、慢性疼痛后的厌恶吗啡和类似焦虑的行为。对于目标 3，我们将检查表达 PVT KOR 的神经元的作用在与压力相关的行为中，通过激活和抑制这些神经元来调节恐惧和厌恶化学遗传学方法。这将是这些表达 PVT KOR 的神经元和 KOR 本身第一次均受到全面调查。确定 KOR 所涉及的神经元回路 KOR+电路的功能意义将增强我们对KOR功能的理解神经解剖学和 KOR 介导的厌恶、焦虑、应激反应和其他精神病理学。这获得的知识可能为开发 KOR 拮抗剂作为抗焦虑剂提供神经元基础。