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

项目概要/摘要 慢性疼痛患者的尼古丁成瘾是一个严重的公共卫生问题，对健康有重大影响。 护理费用和生产力损失。与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，这反过来又与 随着吸烟和电子烟的增加。因此，我推测存在一种神经生物学机制 慢性疼痛会减少中脑边缘多巴胺能信号传导，从而诱发负面情感状态，从而 增加使用尼古丁的风险。研究慢性疼痛和慢性疼痛合并症的因果机制 尼古丁的使用，我建议在大鼠中建立这种合并症模型，并实现以下目标：目标 1：评估腹侧 被盖区 – 伏隔核 (VTA-NAc) 慢性疼痛模型中的多巴胺 (DA) 信号传导 确定 DA 信号传导的减少是否是慢性疼痛引起的负面情感状态的基础。目标 2： 确定与无痛状态相比，尼古丁是否增强了慢性疼痛状态的强化功效 州。该提案结合了行为、药理学、神经化学和光遗传学方法 揭示与慢性疼痛相关的 VTA-NAc DA 信号传导减少是否是慢性疼痛诱发的基础 消极情感状态，以及与无痛状态相比，尼古丁在慢性疼痛状态下是否更有益 由于基线 DA 信号减弱，从而加剧了尼古丁对 DA 信号的影响。 我的总体职业目标是成为一名独立的学术科学家，识别神经生物学机制 根据这些现象为患有共病疼痛和尼古丁的患者制定新的干预措施 成瘾。拟议的 K01 培训将增加我对神经生物学和中脑边缘回路的了解 奖励途径，使我能够研究其在慢性疼痛引起的负面影响和尼古丁中的调节作用 成瘾。我的主要导师阿迪博士是药物滥用和神经生物学和神经化学方面的专家 耶鲁大学科学家多样性和包容性主任将提供有关药物强化机制的培训 和体内伏安法以及对构建包容性和多元化工作环境的见解。我的共同导师 DiLeone 博士是控制奖励相关行为的神经回路专家，他将提供以下方面的培训： 神经调节和体内光遗传学。我的合作导师 Porreca 博士是疼痛引起的情感和疼痛方面的专家 动机行为和奖励回路，将为建模和理解提供培训和监督 慢性疼痛和负面影响中的大脑奖励回路。我的合作导师 Picciotto 博士是少年项目的主任 耶鲁大学精神病学系的教师指导计划将指导我的职业发展 与Addy博士一起接受培训。我的顾问 Ditre 博士是一位人类慢性疼痛合并症方面的专家 尼古丁成瘾将为人类数据的讨论提供见解。我还将接受广泛的培训 参加课程、研讨会、会议和讲习班。通过提出的K01，我将有效地获得新的 技术技能和观点，最终促进成功过渡成为首席研究员。

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.