Pronociceptive and antinociceptive opioid mechanisms in the central nucleus of the amygdala

杏仁核中央核的促痛和抗痛阿片类药物机制

• 批准号: 10441463
• 负责人: Guangchen Ji
• 金额: $ 50.25万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10441463
• 关键词: Acute Pain; Address; Affect; Affective; Amygdaloid structure; Analgesics; Anatomy; Area; Attenuated; Behavior; Brain; Brain Stem; Brain region; Cell Nucleus; Cells; Central Lateral Nucleus; Central Medial Thalamic Nucleus; Characteristics; Clinical Research; Complex; Corticotropin-Releasing Hormone; Data; Development; Electrophysiology (science); Emotional; Female; Future; Genetic; Goals; Health; Impairment; Intercalated Cell; Interneurons; Knowledge; Ligands; Ligation; Mechanics; Mediating; Modeling; Molecular; Motivation; Mus; Neuraxis; Neurobiology; Neuronal Plasticity; Neurons; Nociception; Opioid; Opioid Analgesics; Opioid Antagonist; Opioid Receptor; Opioid agonist; Organism; Output; Pain; Pain Research; Pain quality; Pathologic; Pathway interactions; Peripheral; Population; Positioning Attribute; Prefrontal Cortex; Rattus; Receptor Activation; Receptor Cell; Receptor Inhibition; Receptor Signaling; Reflex action; Role; Sensory; Sex Differences; Signal Transduction; Slice; Spinal nerve structure; Structure; Synapses; Synaptic plasticity; Testing; Therapeutic; Transgenic Mice; United States National Institutes of Health; adaptive learning; animal pain; behavioral outcome; behavioral response; cell type; central sensitization; chronic neuropathic pain; chronic pain; chronic pain management; chronic pain patient; conditioned place preference; drug development; endogenous opioids; experience; innovation; kappa opioid receptors; male; midbrain central gray substance; mouse model; mu opioid receptors; novel; novel therapeutic intervention; novel therapeutics; optogenetics; pain behavior; pain inhibition; pain model; pain receptor; painful neuropathy; preclinical study; presynaptic; receptor; receptor function; response; sensory input; transmission process; vocalization

Project Summary Multiple lines of evidence support wide-spread structural and functional maladaptations in brain circuits as a contributing factor promoting chronic pain. Dysregulation of descending pain modulatory circuits have been demonstrated in chronic pain patients. However, our understanding of the molecular mechanisms and brain circuits that underlie inhibition or facilitation of pain under normal and pathological conditions remains limited. Opioid analgesics engage these brain circuits, but non-addictive options to treat pain are urgently needed. In this proposal, we will investigate pain modulatory mechanisms in the amygdala, a structure involved in integration of pain-related sensory inputs and emotional processing. We will test the hypothesis that functionally opposing endogenous mu (MOR) and kappa (KOR) opioid circuits in the central nucleus of the amygdala (CeA) inhibit or promote, respectively, pain behavior. Bidirectional descending pain modulatory circuits have been characterized most extensively in the rostral ventromedial medulla (RVM). However, little is known about descending modulatory circuits above the brainstem. In the RVM, pro-nociceptive and anti-nociceptive functions are mediated by MOR-expressing “pain ON” cells and KOR-expressing “pain OFF” cells. We propose that similar functional organization with MOR- and KOR-expressing cells serving opponent roles in sensory and/or affective pain behavior also exists in the CeA. Importantly, the reciprocal function of the MOR and KOR circuits may represent a general organizational principle for pain modulation in other brain areas. We will use transgenic mouse models in combination with optogenetic and chemogenetic approaches and anterograde and retrograde tracing for the cell type-specific and projection-specific analysis of MOR and KOR circuits in the CeA and their contribution to pain behaviors in a neuropathic pain model (spinal nerve ligation). Specific Aim 1 will determine the anatomical characteristics of KOR and MOR cells in the CeA. Specific Aim 2 will explore the synaptic and cellular effects of KOR and MOR activation or inhibition and their interaction. Specific Aim 3 will assess the role of MOR and KOR circuits in pain behaviors using reflexive responses (mechanical and thermal thresholds) as well as complex behaviors related to affective and motivational qualities of pain (vocalization, conditioned place preference/avoidance). Eletrophysiological and behavioral outcomes will be assessed with cell specific manipulations under control conditions and in a neuropathic pain model in both male and female mice allowing the determination of possible sex differences in the amygdala circuit. The proposed studies will identify a previously unknown KOR-mediated pro-nociceptive amygdala circuit and its relationship to MOR-mediated anti-nociceptive mechanisms. Impaired MOR signaling and/or increased KOR signaling in the CeA may result in an inhibition-excitation imbalance of descending modulation to promote chronic pain. Importantly, the opposing MOR-KOR function in the CeA would provide the conceptual basis for the development of non-addictive therapies for chronic pain.

项目摘要 多种证据支持脑回路中广泛存在的结构和功能适应不良， 促进慢性疼痛的因素。下行性疼痛调节回路的失调已经被证实是 在慢性疼痛患者中得到证实。然而，我们对分子机制和大脑的理解 在正常和病理条件下抑制或促进疼痛的回路仍然有限。 阿片类镇痛剂参与这些大脑回路，但迫切需要非成瘾性的疼痛治疗方案。 在这个建议中，我们将研究杏仁核中的疼痛调节机制，杏仁核是一种参与 疼痛相关的感觉输入和情绪处理的整合。我们将检验这个假设， 杏仁核中央核（CeA）中内源性μ（莫尔）和κ（KOR）阿片回路的对立 分别抑制或促进疼痛行为。双向下行疼痛调节回路已经被研究， 在延髓头端腹内侧区（RVM）最具特征。然而，人们对 脑干上方的下行调节回路在RVM中，促伤害感受和抗伤害感受功能 由表达MOR的“疼痛开启”细胞和表达KOR的“疼痛关闭”细胞介导。我们建议，类似 功能组织与莫尔-和KOR-表达细胞在感觉和/或情感中担任对立角色 疼痛行为也存在于脑区。重要的是，莫尔和KOR电路的倒数功能可以 代表了其他脑区疼痛调节的一般组织原则。 我们将使用转基因小鼠模型结合光遗传学和化学遗传学方法， 用于莫尔和KOR的细胞类型特异性和投影特异性分析的顺行和逆行追踪 在神经性疼痛模型（脊神经结扎）中，CeA中的回路及其对疼痛行为的贡献。 具体目标1将确定CeA中KOR和莫尔细胞的解剖学特征。具体目标2 将探讨KOR和莫尔激活或抑制的突触和细胞效应及其相互作用。 具体目标3将使用反射反应评估莫尔和KOR回路在疼痛行为中的作用 （机械和热阈值）以及与情感和动机品质相关的复杂行为 疼痛（发声，条件性位置偏好/回避）。电生理和行为结果将 在对照条件下和在神经性疼痛模型中， 雄性和雌性小鼠，以确定杏仁核回路中可能的性别差异。 这项研究将确定一个以前未知的KOR介导的亲伤害性杏仁核回路及其相关机制。 与MOR介导的抗伤害性机制的关系。莫尔信号传导受损和/或KOR升高 CeA中的信号传导可能导致下行调制的抑制-兴奋失衡，以促进慢性炎症。 痛苦重要的是，CeA中相反的MOR-KOR功能将为 开发慢性疼痛的非成瘾疗法。