The Role of Mesoaccumbens Dopamine in Pain and Prescription Opioid Addiction

中伏多巴胺在疼痛和处方阿片类药物成瘾中的作用

• 批准号: 9890635
• 负责人: Amanda Rosemary Pahng
• 金额: --
• 依托单位: SOUTHEAST LOUISIANA VETERANS HEALTH CARE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9890635
• 关键词: Academic support; Acute; Adult; Affect; Age; Agonist; American; Anabolism; Animals; Attenuated; Award; Bathing; Behavior; Behavioral; Biochemical; Brain; Cells; Central Nervous System Diseases; Chronic; Chronic inflammatory pain; Data; Development; Disease; Dopamine; Dose; Electrophysiology (science); Female; Fentanyl; Fostering; Freund' s Adjuvant; Future; Goals; High Prevalence; Hyperalgesia; Impairment; Intake; Intravenous; Investigation; K-Series Research Career Programs; Knowledge; Measures; Mechanics; Mediating; Medical; Mentors; Mentorship; Military Personnel; Modeling; Morphine; Motivation; Neurons; Nociception; Nucleus Accumbens; Operative Surgical Procedures; Opiate Addiction; Opioid; Outcome; Pain; Pain Measurement; Pain management; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Population; Positioning Attribute; Preparation; Process; Productivity; Property; Rattus; Reporting; Research; Research Personnel; Rewards; Role; Scientist; Self Administration; Signal Transduction; Slice; Techniques; Testing; Therapeutic; Training; Treatment Cost; Ventral Striatum; Ventral Tegmental Area; Veterans; Whole-Cell Recordings; Withdrawal; addiction; animal pain; behavioral pharmacology; biobehavior; career; career development; chronic pain; chronic pain patient; cost; designer receptors exclusively activated by designer drugs; disability; dopaminergic neuron; drug of abuse; experimental study; faculty research; fentanyl abuse; illicit opioid; innovation; male; neuronal excitability; novel therapeutic intervention; opioid use; pain sensitivity; pain symptom; pramipexol; pre-clinical research; prescription opioid; prescription opioid addiction; receptor; response; skill acquisition; skills; transmission process

This Veterans Affairs Career Development Award (CDA)-2 will provide support for academic career development through mentored research and professional skills development in preparation for transition to an academic research faculty position. Proposed activities will occur under the mentorship of Drs. Nicholas Gilpin, James Zadina, Scott Edwards, and Tiffany Wills and will foster hypothesis-driven research and independent investigation. Chronic pain affects >100 million American adults, costing the nation ~$635 billion every year in medical treatment costs and lost productivity. Due to the high prevalence of chronic pain among Veterans, treatment of chronic pain is a top priority of the Department of Veteran Affairs (VA), with prescription opioids a critical first-line treatment for chronic pain patients. However, Veterans treated chronically with opioids for their chronic pain may be vulnerable to developing opioid addiction and/or using illicit opioids to self-medicate pain symptoms. Chronic pain and opioid addiction each produce functional abnormalities in the nucleus accumbens (NAc), including dopamine (DA) deficits, which may be attributable to reduced cell firing of ventral tegmental area (VTA) DA neurons projecting to the NAc. The NAc mediates the acute rewarding effects of drugs of abuse via the mesoaccumbens pathway (VTA to NAc) and represents a functional terminus for ascending nociceptive pathways. However, there remains a gap in our knowledge regarding how chronic pain and limited/escalated opioid use interact to alter NAc neuronal excitability, drug intake, and pain sensitivity. The purpose of this project is to examine overlapping brain biochemical mechanisms of chronic pain and opioid dependence that may contribute to the worsening and potential interdependence of these two disorders. Our central hypothesis is that chronic pain induces mesolimbic dopaminergic signaling deficits that drive the development of prescription opioid (i.e., fentanyl) abuse, and fentanyl intake exaggerates pain-like outcomes in rats with chronic inflammatory pain. Here we propose that I) chronic inflammatory pain increases fentanyl intake, and that fentanyl intake exaggerates hyperalgesia in rats with chronic inflammatory pain, II) chronic inflammatory pain and fentanyl intake each increase the intrinsic excitability of NAc neurons and excitatory transmission onto NAc neurons, and III) VTA- NAc DA circuit activation and/or D2-like receptor agonist treatment each reduce hyperalgesia and escalated fentanyl intake in rats with chronic inflammatory pain. These hypotheses reflect the order of the aims in this CDA proposal. To investigate these hypotheses, we propose an innovative experimental strategy that compares the effects of chronic inflammatory pain states on the electrophysiological properties of NAc neurons and behavioral deficits (fentanyl intake/motivation, nociception) in animals given long access (LgA; 12 hrs) to fentanyl and short access (ShA; 1 hr) to fentanyl. Finally, we will use chemogenetics and targeted pharmacotherapies to test the effects of VTA-NAc DA circuit activation and D2-like receptor agonism on fentanyl intake/motivation and nociceptive measures in rats with chronic inflammatory pain. Conclusions resulting from these studies will have an important impact within both the pain management and addiction fields, as well as provide potential pharmacotherapeutic strategies for VA populations suffering from chronic pain and opioid addiction. In addition, an important feature of this CDA proposal is its provision of training in critical skills necessary for the applicant to attain her long-term goal of becoming an independent biomedical researcher and leader in the field of pain and opioid addiction research. Career development milestones and trajectories will guide her progression to an independent VA research career and include a transition to independence in terms of behavioral, surgical, electrophysiological, pharmacological, and chemogenetic techniques as well as a critical focus on professional skills development. In summary, this CDA award will greatly facilitate the applicant’s transition to an independent VA research position to continue future investigations into the biobehavioral mechanisms of chronic pain and opioid addiction.

退伍军人事务部职业发展奖 (CDA)-2 将为学术职业发展提供支持 通过指导研究和专业技能发展，为向学术过渡做好准备 研究教员职位。拟议的活动将在博士的指导下进行。尼古拉斯·吉尔平、詹姆斯 Zadina、Scott Edwards 和 Tiffany Wills 将促进假设驱动的研究和独立研究 调查。慢性疼痛影响超过 1 亿美国成年人，每年给国家造成约 6,350 亿美元的损失 医疗费用和生产力损失。由于退伍军人中慢性疼痛的患病率很高， 治疗慢性疼痛是退伍军人事务部 (VA) 的首要任务，处方阿片类药物 慢性疼痛患者的关键一线治疗。然而，退伍军人长期使用阿片类药物治疗 慢性疼痛可能容易出现阿片类药物成瘾和/或使用非法阿片类药物自我治疗疼痛 症状。慢性疼痛和阿片类药物成瘾都会导致伏隔核功能异常 （NAc），包括多巴胺（DA）缺乏，这可能是由于腹侧被盖细胞放电减少所致 区域 (VTA) DA 神经元投射到 NAc。 NAc 介导滥用药物的急性奖赏效应 通过中伏隔通路（VTA 至 NAc），代表上行伤害感受的功能终点 途径。然而，关于慢性疼痛和有限/升级的情况，我们的知识仍然存在差距。 阿片类药物的使用会相互作用，改变 NAc 神经元的兴奋性、药物摄入量和疼痛敏感性。该项目的目的 是为了检查慢性疼痛和阿片类药物依赖的重叠大脑生化机制，这可能是 导致这两种疾病的恶化和潜在的相互依赖性。我们的中心假设是 慢性疼痛会引起中脑边缘多巴胺能信号缺陷，从而推动处方阿片类药物的开发 （即芬太尼）滥用，芬太尼的摄入会加剧慢性炎性疼痛大鼠的疼痛样结果。 在这里我们建议I)慢性炎症性疼痛会增加芬太尼的摄入量，并且芬太尼的摄入量会夸大 慢性炎性疼痛大鼠的痛觉过敏，II) 慢性炎性疼痛和芬太尼摄入量各 增加 NAc 神经元的内在兴奋性和 NAc 神经元的兴奋性传递，以及 III) VTA- NAc DA 回路激活和/或 D2 样受体激动剂治疗均可减轻痛觉过敏并加剧 慢性炎性疼痛大鼠的芬太尼摄入量。这些假设反映了本 CDA 中目标的顺序 提议。为了研究这些假设，我们提出了一种创新的实验策略，该策略比较了 慢性炎症疼痛状态对 NAc 神经元电生理特性和行为的影响 给予长期（LgA；12小时）芬太尼和短期接触芬太尼的动物的缺陷（芬太尼摄入/动机、伤害感受） 获得芬太尼（ShA；1小时）。最后，我们将使用化学遗传学和靶向药物疗法来测试 VTA-NAc DA 回路激活和 D2 样受体激动对芬太尼摄入/动机的影响 患有慢性炎症疼痛的大鼠的伤害性措施。这些研究得出的结论将 在疼痛管理和成瘾领域产生重要影响，并提供潜力 针对患有慢性疼痛和阿片类药物成瘾的 VA 人群的药物治疗策略。此外， 该 CDA 提案的一个重要特点是为申请人提供了必要的关键技能培训 实现成为独立生物医学研究员和疼痛领域领导者的长期目标 和阿片类药物成瘾研究。职业发展里程碑和轨迹将引导她走向职业生涯 独立的 VA 研究生涯，包括在行为、外科、 电生理学、药理学和化学遗传学技术以及对专业的关键关注 技能发展。综上所述，本次CDA奖项将极大地促进申请人向独立的过渡 VA 研究的定位是继续未来对慢性疼痛和慢性疼痛的生物行为机制的研究 阿片类药物成瘾。