Chronic Pain Modulation of Mesolimbic Dopamine Signaling for Natural and Opiate Rewards

中脑边缘多巴胺信号传导的慢性疼痛调节对天然和阿片类药物的奖励

• 批准号: 10620197
• 负责人: Gabriela Carolina Lopez
• 金额: $ 4.29万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10620197
• 关键词: Absence of pain sensation; Acute; Acute Pain; Affective; Animal Model; Association Learning; Behavior; Behavioral; Biological; Brain; Cues; Data; Depressed mood; Dopamine; Drug Addiction; Drug abuse; Drug usage; Educational process of instructing; Extinction; Fentanyl; Fiber; Food; Functional disorder; Future; Goals; Grant; Injury; Knowledge; Lead; Learning; Life; Longevity; Manuscripts; Measures; Mediating; Mental Depression; Mentorship; Minority-Serving Institution; Modeling; Mood Disorders; Motivation; Mus; National Institute of Drug Abuse; National Research Service Awards; Neurobiology; Nose; Nucleus Accumbens; Operant Conditioning; Opiate Addiction; Opioid; Outcome; Overdose; Pain; Patients; Persons; Pharmacotherapy; Photometry; Postdoctoral Fellow; Predisposition; Psychological reinforcement; Public Health; Research Personnel; Rewards; Risk; Role; Scientist; Signal Transduction; Sucrose; Testing; Thinking; Training; United States; United States Dept. of Health and Human Services; Ventral Tegmental Area; Writing; abuse liability; addiction; anxious; approach behavior; behavioral response; brain circuitry; chronic pain; chronic pain management; chronic painful condition; design; disability; experience; experimental study; in vivo; mouse model; negative affect; nerve injury; neural; optogenetics; oral communication; pain chronification; pain model; painful neuropathy; prescription opioid; prevent; rumination; sham surgery; spared nerve; vapor

Project Summary/Abstract Chronic pain is a debilitating condition that causes long-term disability. Chronic pain causes negative affective states that often lead to anxious ruminating thoughts and depressed mood, where patients have to constantly decide between behaviors that minimize pain but restrict daily life or to persevere through pain. Current treatments for chronic pain often involve prescription opioids. While prescription opioids provide much needed analgesia, opioids also have a high abuse potential that puts patients at risk of developing an opioid addiction. The motivational-affective changes caused by chronic pain indicate that this debilitating condition itself may increase risk for opioid addiction. Chronic pain and affective disorders show dysfunction within the nucleus accumbens core (cNAc), a region in the brain’s reward circuit that receives dopaminergic inputs from the ventral tegmental area (VTA) and has a significant role in motivation and learning of cue-reward associations. I hypothesize that chronic pain (1) increases the addictive potential of opioids through changes in dopamine signaling that increase the strength of learned positive cue associations, and (2) increases motivation to obtain opioid rewards. In this proposal, I will test how learned positive cue associations and motivational effort for obtaining opioid rewards is altered by pain. In Aim 1, I will use a neuropathic pain animal model, Pavlovian conditioning for a sucrose reward, and in vivo fiber photometry to test the effect of untreated acute and chronic pain on VTA to cNAc dopamine signaling during extinction and reinstatement for a food reward. In Aim 2, I will use the same pain model in conjunction with in vivo fiber photometry to examine how chronic pain changes VTA to cNAc dopamine signaling during an operant task for opioid reward. Results from these experiments will aid in identifying behavioral and neurobiological interactions between pain and opioid addiction. My proposal, in accordance with NIDA’s goals, would aid in identifying the biological and behavioral causes and consequences of drug use and addiction across the lifespan. Under this training grant, I plan to receive training in oral communication, teaching, grant and manuscript writing, programming, and further knowledge of drug abuse and addiction. My past experiences, my current training plans, and my mentorship team make me the ideal candidate for receiving an NRSA. I intend to use the opportunities and training provided by this grant to become a competitive postdoctoral fellow and, eventually, successful independent researcher at a liberal arts minority-serving institution.

项目概要/摘要 慢性疼痛是一种使人衰弱的疾病，会导致长期残疾。慢性疼痛会导致负面情绪 经常导致焦虑、沉思和抑郁情绪的状态，患者必须不断地 在减少疼痛但限制日常生活的行为和忍受疼痛的行为之间做出选择。当前的 慢性疼痛的治疗通常涉及处方阿片类药物。虽然处方阿片类药物提供了急需的 除了镇痛之外，阿片类药物也具有很高的滥用潜力，使患者面临阿片类药物成瘾的风险。 慢性疼痛引起的动机-情感变化表明，这种使人衰弱的状况本身可能会导致 增加阿片类药物成瘾的风险。慢性疼痛和情感障碍显示核内功能障碍 伏隔核（cNAc），大脑奖励回路中的一个区域，接收来自大脑的多巴胺能输入 腹侧被盖区（VTA），在动机和提示奖励关联的学习中具有重要作用。我 假设慢性疼痛 (1) 通过多巴胺的变化增加阿片类药物的成瘾潜力 发出信号，增加习得的积极线索关联的强度，并且（2）增加获得的动力 阿片类药物奖励。在这个提案中，我将测试如何学习积极的线索关联和激励努力 获得阿片类药物的奖励会因疼痛而改变。在目标 1 中，我将使用神经性疼痛动物模型，巴甫洛夫模型 蔗糖奖励调节，以及体内纤维光度测定，以测试未经治疗的急性和慢性的效果 在食物奖励的灭绝和恢复过程中，VTA 到 cNAc 多巴胺信号传导的疼痛。在目标 2 中，我将 使用相同的疼痛模型结合体内纤维光度测定来检查慢性疼痛如何变化 在阿片类药物奖励的操作任务中，VTA 到 cNAc 多巴胺信号传导。这些实验的结果将 帮助识别疼痛和阿片类药物成瘾之间的行为和神经生物学相互作用。我的建议， 根据 NIDA 的目标，将有助于确定生物学和行为原因以及 整个生命周期中吸毒和成瘾的后果。根据这笔培训补助金，我计划接受培训 口头交流、教学、资助和手稿写作、编程以及药物进一步知识 滥用和成瘾。我过去的经历、我当前的培训计划和我的导师团队使我成为 获得 NRSA 的理想候选人。我打算利用这笔赠款提供的机会和培训 成为一名有竞争力的博士后研究员，并最终成为文科领域成功的独立研究员 为少数族裔服务的机构。