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: 10463979
• 负责人: Gabriela Carolina Lopez
• 金额: $ 4.2万
• 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/10463979
• 关键词: Absence of pain sensation; Acute; Acute Pain; Address; Affective; Animal Model; Behavior; Behavioral; Biological; Brain; Cues; Data; Depressed mood; Dopamine; Drug Addiction; Drug abuse; Drug usage; Educational process of instructing; Extinction (Psychology); 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; 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; classical conditioning; design; disability; experience; experimental study; in vivo; mouse model; negative affect; nerve injury; optogenetics; oral communication; pain chronification; pain model; painful neuropathy; prescription opioid; prevent; relating to nervous system; 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.

项目总结/摘要 慢性疼痛是一种使人衰弱的疾病，会导致长期残疾。慢性疼痛导致消极情感 状态，往往会导致焦虑的反刍思想和抑郁的情绪，患者必须不断 在尽量减少疼痛但限制日常生活的行为之间做出决定，或者在疼痛中坚持下去。电流 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 阿片类药物具有镇痛作用，但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。 由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 增加阿片类药物成瘾风险。慢性疼痛和情感障碍表现为核内功能障碍 多巴胺核心（cNAc）是大脑奖赏回路中的一个区域，它从多巴胺受体接受多巴胺能输入。 腹侧被盖区（VTA），并在动机和线索奖励协会的学习中发挥重要作用。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 信号，增加学习积极线索协会的强度，（2）增加动机，以获得 阿片类药物奖励在这个建议中，我将测试如何学习积极的线索协会和动机的努力， 获得阿片类药物的奖励会因疼痛而改变。在目标1中，我将使用神经病理性疼痛动物模型，巴甫洛夫 调节蔗糖奖励，并在体内纤维光度测定法，以测试未经处理的急性和慢性 疼痛对腹侧被盖区cNAc多巴胺信号在灭绝和恢复食物奖励。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性任务期间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。我的提议， 根据NIDA的目标，将有助于确定生物和行为原因， 药物使用和成瘾的后果。在此培训补助金下，我计划接受培训 在口头交流、教学、赠款和手稿写作、编程和进一步了解药物方面 滥用和成瘾。我过去的经验，我目前的培训计划，以及我的导师团队使我成为 获得NRSA的理想人选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，并最终成为一名成功的文科独立研究员。 少数民族服务机构。