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

项目摘要/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，具有重要的健康意义。 护理费用和工作效率损失。慢性疼痛相关的负面情绪状态，如焦虑，是一种风险 影响烟草使用的因素。更大的慢性疼痛强度增加了对焦虑的敏感性，而焦虑反过来又与 随着吸烟和吸食电子烟的增多。因此，我假设存在一种神经生物学机制 慢性疼痛使中脑边缘多巴胺能信号减弱，从而导致产生负面情绪状态。 增加尼古丁的使用风险。探讨慢性疼痛与慢性疼痛共病的致病机制。 尼古丁的使用，我建议在大鼠身上建立这种共病的模型，目的如下：目的1：评估腹侧 被盖区-伏核(VTA-NAC)多巴胺(DA)信号在慢性疼痛模型中的作用 确定DA信号的减少是否是慢性疼痛引起的负面情绪状态的基础。目标2： 确定与单纯疼痛相比，尼古丁在慢性疼痛状态下是否增强了增强效果 各州。这项建议结合了行为学、药理学、神经化学和光遗传学的方法来 揭示慢性疼痛相关的VTA-NAC DA信号的减少是否是慢性疼痛诱导的基础 消极的情感状态，以及尼古丁在慢性疼痛状态下是否比天真的疼痛更有回报 由于基线DA信号减少，尼古丁对DA信号的影响进一步恶化。 我的整个职业目标是成为一名独立的学术科学家，研究神经生物学机制 根据这些现象开发新的干预措施来治疗合并疼痛和尼古丁的患者 上瘾。建议的K01训练将增加我对中脑边缘神经生物学和神经回路的知识。 奖赏途径，使我能够研究其在慢性疼痛诱导的负面情绪和尼古丁中的中介作用 上瘾。我的主要导师艾迪博士是药物滥用的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关于药物强化机制的培训 以及体内伏安法，以及对构建包容和多样化的工作环境的洞察力。我的合作导师 迪里昂博士是控制奖赏相关行为的神经元回路方面的专家，他将提供以下培训 神经调节和体内光遗传学。我的另一位导师波雷卡博士，一位疼痛诱导情感和 激励行为和奖励回路，将提供建模和理解方面的培训和监督 慢性疼痛和消极情绪中的大脑奖赏回路。我的合作导师皮乔托博士，青少年医院的主任 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 和艾迪医生一起训练。我的顾问Ditre博士是人类慢性疼痛共病方面的专家 尼古丁成瘾，将为人类数据的讨论提供洞察力。我还将接受广泛的培训，通过 参加课程、研讨会、会议和研讨会。通过建议的K01，我将有效地获得新的 技术技能和视角，最终促进成功过渡成为首席调查员。

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.