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

基本信息

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
项目类别：
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

项目摘要

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，导致负面情感。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当前疼痛的行为之间做出选择。慢性疼痛的治疗通常涉及处方阿片类药物，而处方阿片类药物可提供急需的药物。除了止痛之外，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），在提示-奖励关联的动机和学习中具有重要作用。认为慢性疼痛 (1) 通过多巴胺的变化增加阿片类药物的成瘾潜力信号传递可以增加习得的积极线索关联的强度，并且（2）增加获得的动力在这个提案中，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影响在目标 2 中，我会在灭绝和恢复过程中对 VTA 至 cNAc 多巴胺信号产生疼痛。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期间，VTA 到 cNAc 多巴胺信号传导将来自这些实验。帮助确定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。根据 NIDA 的目标，将有助于确定生物学和行为原因以及根据这项培训补助金，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我过去的经历、我目前的训练计划和我的指导团队使我成为了获得 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。