Involvement of dopamine signaling in chronic pain-induced negative affective state and nicotine use comorbidity

多巴胺信号传导参与慢性疼痛引起的负面情感状态和尼古丁使用合并症

基本信息

批准号：
10662951
负责人：
Deniz Bagdas
金额：
$ 18万
依托单位：
YALE UNIVERSITY
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：
2023-04-01 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10662951
关键词：
Address Adult Affective Affective Symptoms Anabolism Anhedonia Animals Anxiety Attenuated Behavior Behavioral Binding Biological Assay Brain Chronic intense pain Corpus striatum structure DRD2 gene Data Development Dimensions Disease Dopamine Dopamine Antagonists Dopamine D2 Receptor Educational workshop Goals Health Care Costs Healthcare Human Individual Infusion procedures Intake Intervention Intravenous Investigation Knowledge Maintenance Measures Mediating Mediation Mental Depression Mentors Modeling Mood Disorders Morphine Motivation Neurobehavioral Manifestations Neurobiology Nicotine Nicotine Dependence Nicotine Use Disorder Nucleus Accumbens Pain Pathway interactions Patients Periodicity Pre-Clinical Model Principal Investigator Productivity Psychiatry Psychological reinforcement Public Health Rattus Recording of previous events Reporting Research Rewards Risk Risk Factors Scanning Scientist Self Administration Sensory Signal Transduction Smoking Substance abuse problem Technical Expertise Therapeutic Intervention Tobacco use Training Ventral Tegmental Area Work abuse liability anxiety-like behavior career chronic pain chronic pain patient comorbidity diversity and inclusion dopaminergic neuron drug reinforcement experience extracellular faculty mentor high reward human data in vivo insight negative affect neurobiological mechanism neurochemistry neuronal circuitry neuroregulation nicotine exposure nicotine self-administration nicotine use optogenetics pain sensitivity personalized therapeutic pharmacologic professional atmosphere programs reward circuitry symposium therapeutic development vaping

Address Adult Affective Affective Symptoms Anabolism Anhedonia Animals Anxiety Attenuated Behavior Behavioral Binding Biological Assay Brain Chronic intense pain Corpus striatum structure DRD2 gene Data Development Dimensions Disease Dopamine Dopamine Antagonists Dopamine D2 Receptor Educational workshop Goals Health Care Costs Healthcare Human Individual Infusion procedures Intake Intervention Intravenous Investigation Knowledge Maintenance Measures Mediating Mediation Mental Depression Mentors Modeling Mood Disorders Morphine Motivation Neurobehavioral Manifestations Neurobiology Nicotine Nicotine Dependence Nicotine Use Disorder Nucleus Accumbens Pain Pathway interactions Patients Periodicity Pre-Clinical Model Principal Investigator Productivity Psychiatry Psychological reinforcement Public Health Rattus Recording of previous events Reporting Research Rewards Risk Risk Factors Scanning Scientist Self Administration Sensory Signal Transduction Smoking Substance abuse problem Technical Expertise Therapeutic Intervention Tobacco use Training Ventral Tegmental Area Work abuse liability anxiety-like behavior career chronic pain chronic pain patient comorbidity diversity and inclusion dopaminergic neuron drug reinforcement experience extracellular faculty mentor high reward human data in vivo insight negative affect neurobiological mechanism neurochemistry neuronal circuitry neuroregulation nicotine exposure nicotine self-administration nicotine use optogenetics pain sensitivity personalized therapeutic pharmacologic professional atmosphere programs reward circuitry symposium therapeutic development vaping

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项目摘要

Project Summary/Abstract Nicotine addiction among individuals with chronic pain is a serious public health concern with significant health- care expenses and lost productivity. Chronic pain-associated negative affective state, such as anxiety, is a risk factor for tobacco use. Greater chronic pain intensity increases sensitivity to anxiety, which is, in turn, associated with increased smoking and vaping. Therefore, I hypothesize there is a neurobiological mechanism in which chronic pain decreases mesolimbic dopaminergic signaling to causally induce a negative affective state, thereby increasing the risk of nicotine use. To investigate this causal mechanism in the comorbidity of chronic pain and nicotine use, I propose modeling this comorbidity in rats and the following aims: Aim 1: Evaluate ventral tegmental area – nucleus accumbens (VTA-NAc) dopamine (DA) signaling in a model of chronic pain to determine whether decreases in DA signaling underlie the chronic pain-induced negative affective state. Aim 2: Determine whether nicotine has increased reinforcing efficacy in chronic pain states compared to pain-naïve states. This proposal combines behavioral, pharmacological, neurochemical, and optogenetic approaches to reveal whether chronic pain-associated decreases in VTA-NAc DA signaling underlie chronic pain-induced negative affective states, and whether nicotine is more rewarding in chronic pain states compared to pain-naïve states due to decreased baseline DA signaling, thereby exacerbating nicotine’s effects on DA signaling. My overall career goal is to become an independent academic scientist, identifying neurobiological mechanisms underlying these phenomena to develop new interventions for patients with co-morbid pain and nicotine addiction. The proposed K01 trainings will increase my knowledge of neurobiology and circuitry of the mesolimbic reward pathway, allowing me to investigate its mediation in chronic pain-induced negative affect and nicotine addiction. My primary mentor Dr. Addy, an expert in neurobiology and neurochemistry of substance abuse and Director of Scientist Diversity and Inclusion at Yale, will provide training on mechanisms of drug reinforcement and in vivo voltammetry along with insight into building an inclusive and diverse work environment. My co-mentor Dr. DiLeone, an expert in neuronal circuits controlling reward-related behaviors, will provide training on neuromodulation and in vivo optogenetics. My co-mentor Dr. Porreca, an expert in pain-induced affective and motivational behaviors and reward circuits, will provide training and oversight on modeling and understanding brain reward circuitry in chronic pain and negative affect. My co-mentor Dr. Picciotto, the director of the Junior Faculty Mentoring Program for the Department of Psychiatry at Yale, will mentor my career enhancement trainings together with Dr. Addy. My consultant Dr. Ditre, an expert in human comorbidity of chronic pain and nicotine addiction, will provide insights in the discussions of human data. I will also receive extensive training by attending courses, seminars, conferences, and workshops. Through the proposed K01, I will effectively gain new technical skills and perspectives, ultimately facilitating a successful transition to become a principal investigator.

项目摘要/摘要慢性疼痛患者中的尼古丁成瘾是一个严重的公共卫生关注的问题护理费用和生产力失去。慢性疼痛相关的负面情感状态（例如焦虑）是一种风险烟草使用的因素。更大的慢性疼痛强度会增加对焦虑的敏感性，这反过来又相关随着吸烟和烟的增加。因此，我假设有一种神经生物学机制慢性疼痛会降低中唇多巴胺能信号传导，从而引起负面的情感状态增加使用尼古丁的风险。在慢性疼痛和使用尼古丁，我建议在大鼠中建模这种合并症，以下目的：目标1：评估腹侧细分区域 - 伏击核（VTA-NAC）多巴胺（DA）信号在慢性疼痛模型中确定DA信号的降低是否是慢性疼痛引起的负面情感状态的基础。目标2：与没有疼痛相比国家。该提案结合了行为，药物，神经化学和光遗传学方法揭示VTA-NAC DA信号传导中慢性疼痛相关的下降是慢性疼痛引起的与没有疼痛的慢性疼痛状态相比国家由于基线DA信号的降低而加剧了尼古丁对DA信号的影响。我的整体职业目标是成为一名独立的学术科学家，确定神经生物学机制这些现象的基础，以开发新的干预措施，以针对疼痛和尼古丁的患者进行新的干预措施瘾。拟议的K01培训将增加我对中唇的神经生物学和电路的了解奖励途径，使我能够调查其在慢性疼痛引起的负面影响和尼古丁中的调解瘾。我的主要导师Addy博士，神经生物学和药物滥用神经化学专家耶鲁大学的科学家多样性和包容总监将提供有关毒品增强机制的培训以及体内伏安法，以及建立包容性和潜水员的工作环境的洞察力。我的联合委员控制与奖励相关的行为的神经元电路专家迪琳博士将提供有关神经调节和体内光遗传学。我的同事Porreca博士，疼痛引起的情感和动机行为和奖励电路，将为建模和理解提供培训和监督慢性疼痛和负面影响的大脑奖励电路。我的同事Picciotto博士，大三的主任耶鲁大学精神病学系的教师指导计划将我的职业增强与Addy博士一起培训。我的顾问Ditre博士，慢性疼痛和人类合并症专家尼古丁成瘾将为人类数据的讨论提供见解。我还将获得广泛的培训参加课程，半手，会议和讲习班。通过拟议的K01，我将有效地获得新的技术技能和观点，最终支持成功成为首席研究员的过渡。