Alcohol Dependence and Pain: Role of Cingulate Cortex Glucocorticoid Receptors

酒精依赖和疼痛：扣带皮层糖皮质激素受体的作用

• 批准号: 9469962
• 负责人: Mary Adrienne McGinn
• 金额: $ 3.59万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2019-08-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9469962
• 关键词: Affect; Affective; Age; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcohols; Amygdaloid structure; Animal Model; Animals; Anxiety; Attenuated; Behavior; Behavioral; Biological Assay; Brain; Cannulations; Chemosensitization; Chronic; Clinical Research; Clinical Trials; Cognitive; Conflict (Psychology); Data; Dependence; Development; Dimensions; Doctor of Philosophy; Emotional; Environment; Ethanol; Fellowship; Female; Future; Genetic Transcription; Glucocorticoid Receptor; Glucocorticoids; Growth and Development function; Health; Health Sciences; Heavy Drinking; Human; Hyperalgesia; Hypersensitivity; Immunohistochemistry; Incidence; Individual; Intake; Interneurons; Investigation; Label; Maintenance; Measures; Mechanics; Mediating; Mediator of activation protein; Mental disorders; Mentors; Methods; Microinjections; Mifepristone; Modeling; Molecular; Morbidity - disease rate; Motivation; Motor; Negative Reinforcements; Neurobiology; Neurons; Neurosciences; Nociception; Nuclear; Pain; Persistent pain; Pharmaceutical Preparations; Phosphorylation; Physiology; Placebos; Population; Pre-Clinical Model; Preparation; Procedures; Process; Property; Psychological reinforcement; Rattus; Receptor Signaling; Relapse; Reporting; Research; Research Infrastructure; Research Training; Rodent; Rodent Model; Role; Scientist; Sensory; Signal Transduction; Site; Stress; Students; Symptoms; System; Testing; Therapeutic; Training; Withdrawal; Woman; Work; alcohol comorbidity; alcohol craving; alcohol exposure; alcohol research; alcohol seeking behavior; alcohol use disorder; biobehavior; calmodulin-dependent protein kinase II; career; chronic pain; cingulate cortex; drinking; dysphoria; effective therapy; experience; experimental study; glucocorticoid receptor alpha; hippocampal pyramidal neuron; innovation; insight; male; men; negative affect; negative emotional state; neuroadaptation; neurobiological mechanism; novel; pain symptom; pre-clinical; problem drinker; sex; training opportunity; transmission process; treatment strategy; vapor

Abstract _ Approximately 51% of people over the age of 12 are drinkers (120 million), and of these current users, 13.9% have met the criteria for alcohol use disorder (AUD). Severe AUD is a chronic, relapsing psychiatric disorder that is characterized by the emergence of negative emotional states (e.g., dysphoria, anxiety, pain) and the development of negative motivational symptoms (e.g., escalation of drug intake and compulsive drug seeking). This transition from recreational, limited intake to uncontrolled, escalated intake is proposed to involve a transition from positive to negative reinforcement mechanisms for seeking alcohol. Accordingly, alcohol may be sought after and taken in excessive amounts to alleviate the negative, withdrawal-related symptoms. Our rodent model of alcohol dependence reliably demonstrates escalated alcohol drinking and alcohol seeking during withdrawal. Importantly, we have also identified the emergence of significant pain hypersensitivity (or hyperalgesia) in dependent animals, which may serve as a key negative reinforcement mechanism. During alcohol withdrawal, the robust escalation of drinking and hyperalgesia in dependent animals is associated with an increase in central brain glucocorticoid receptor (GR) signaling, a key mediator of stress responsiveness. Importantly, systemic GR antagonism via mifepristone reduces alcohol-mediated hyperalgesia as well as escalated drinking in both preclinical animal models as well as early clinical trials. The main research objective of the current proposal is to investigate the convergence of central nociceptive and alcohol-seeking biobehavioral mechanisms in promoting and/or maintaining the alcohol-dependent state. Our preliminary work has identified an increase in GR phosphorylation within the cingulate cortex of alcohol-dependent rats, and we hypothesize a specific role for increased cingulate glucocorticoid activity in the promotion of both excessive drinking and hyperalgesia. This proposal will provide a promising PhD student with vital research training through studies that use an integrative approach to test the predictions that: 1) alcohol dependence-related escalation of drinking and hyperalgesia is mediated by GR signaling within the cingulate, and 2) alcohol dependence-related potentiation of in GR activity in the cingulate cortex is localized to “pro-nociceptive” excitatory pyramidal neurons and can be attenuated with mifepristone-mediated GR antagonism. These experiments will train a future independent scientist in the functional analysis of candidate mechanisms underlying alcohol dependence and chronic pain. The results of these studies will provide a greater understanding of the neurobiology of alcohol use disorder and an emerging therapeutic, and will additionally contribute to the development of effective treatment strategies for comorbid AUD and pain, leading to improvements in health and decreased morbidity of affected individuals.

摘要_ 大约51%的12岁以上的人是饮酒者(1.2亿)，而在这些目前的饮酒者中，13.9% 已达到酒精使用障碍(AUD)的标准。严重的AUD是一种慢性、复发性的精神障碍 它的特征是出现负面情绪状态(例如，烦躁、焦虑、疼痛)和 出现消极的激励症状(例如，吸食毒品增加和强迫寻求毒品)。 这种从娱乐性的、有限的摄入量向不受控制的、逐步增加的摄入量的转变，被提议涉及 从积极的强化机制过渡到消极的酒精强化机制。因此，酒精可能是 被追捧并过量服用，以缓解与戒断相关的阴性症状。我们的 酒精依赖的啮齿动物模型可靠地显示了饮酒和寻酒行为的升级 在戒烟期间。重要的是，我们还发现出现了显著的疼痛过敏(或 痛觉过敏)，这可能是一个关键的负面强化机制。在.期间 酒精戒断，依赖动物饮酒和痛觉过敏的强劲升级与 中枢脑糖皮质激素受体(GR)信号的增加，这是应激反应的关键媒介。 重要的是，通过米非司酮的全身性GR拮抗可以减少酒精介导的痛觉过敏 在临床前动物模型和早期临床试验中，饮酒量都有所增加。主要研究目标 目前的建议是调查中枢伤害性感受和酒精寻求的汇聚 促进和/或维持酒精依赖状态的生物行为机制。我们的前期工作 已经发现酒精依赖大鼠扣带回皮质GR磷酸化增加，我们 假设扣带回糖皮质激素活性增加对两者的过度促进有特定作用 酗酒和痛觉过敏。这项提议将为有前途的博士生提供重要的研究培训。 通过使用综合方法来检验以下预测：1)与酒精依赖有关 饮酒和痛觉过敏的升级是由扣带回内的GR信号和2)酒精介导的 扣带回皮质内INGR活性的依赖相关增强定位于“伤害性感受” 兴奋性锥体神经元，可被米非司酮介导的GR拮抗作用减弱。这些 实验将培养未来的独立科学家，进行候选机构的功能分析 潜在的酒精依赖和慢性疼痛。这些研究的结果将提供更大的 了解酒精使用障碍的神经生物学和一种新的治疗方法，并将另外 有助于制定有效的AUD和疼痛治疗策略，导致 改善健康状况，降低受影响个人的发病率。