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：
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
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/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

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.

项目摘要/摘要慢性疼痛是导致长期残疾的一种使人衰弱的疾病。慢性疼痛会引起负面情感那些经常导致焦虑的思想和情绪低落的国家，患者必须不断在最小化疼痛但限制日常生活或通过疼痛持续的行为之间做出决定。当前的慢性疼痛的治疗通常涉及处方OOID。虽然处方Ooids提供了急需的镇痛，OOIDS也具有很高的滥用潜力，使患者处于发展OID成瘾的风险。慢性疼痛引起的动机性变化，表明这种使人衰弱的状况本身可能增加阿片类药物成瘾的风险。慢性疼痛和情感障碍在细胞核内显示功能障碍伏隔元（CNAC），大脑奖励电路中的一个区域，从腹侧对接区域（VTA），在动机和学习提示奖励关联中起着重要作用。我假设慢性疼痛（1）通过多巴胺的变化增加阿片类药物的添加剂发信号会增加学习阳性提示关联的强度，并且（2）增加了获得的动力阿片类药物奖励。在此提案中，我将测试如何学习积极的提示协会和动机努力获得阿片类药物奖励会因疼痛而改变。在AIM 1中，我将使用神经性疼痛动物模型Pavlovian 蔗糖奖励的条件和体内纤维光度法，以测试未经治疗的急性和慢性的效果在扩展和恢复食物奖励期间，VTA对CNAC多巴胺信号传导的疼痛。在AIM 2中，我会将相同的疼痛模型与体内纤维光度法结合使用，以检查慢性疼痛如何变化 VTA到CNAC多巴胺在操作任务期间的阿片类药物奖励。这些实验的结果将有助于确定疼痛与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在整个生命周期中吸毒和成瘾的后果。根据这项培训补助金，我计划接受培训在口头交流，教学，授予和手稿写作，编程以及进一步的毒品知识虐待和成瘾。我过去的经验，目前的培训计划以及我的精通团队使我成为接收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，并最终成为文理艺术的成功独立研究员少数派服务机构。