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: 10454093
• 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/10454093
• 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; United States Department of Veterans Affairs; Ventral Striatum; Ventral Tegmental Area; Veterans; Whole-Cell Recordings; Withdrawal; abuse liability; addiction; animal pain; behavioral pharmacology; biobehavior; career; career development; chronic pain; chronic pain management; chronic pain patient; cost; designer receptors exclusively activated by designer drugs; dopaminergic neuron; drug of abuse; experimental study; faculty research; fentanyl abuse; illicit opioid; innovation; male; military veteran; neuronal excitability; novel therapeutic intervention; opioid use; pain sensitivity; pain symptom; pain-related disability; 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.

这个退伍军人事务发展奖（CDA）-2将为学术职业发展提供支持 通过指导的研究和专业技能发展，准备过渡到学术 研究教师职位。拟议的活动将在博士的心态下发生。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 投资。慢性疼痛影响> 1亿美国成年人，每年耗资6350亿美元 医疗费用和生产力失去。由于退伍军人慢性疼痛的患病率很高， 慢性疼痛的治疗是退伍军人事务部（VA）的重中之重，处方阿片类药物 慢性疼痛患者的关键一线治疗。但是，退伍军人治疗了钟表 慢性疼痛可能很容易发生阿片类药物成瘾和/或使用非法阿片类药物自我药物疼痛 症状。慢性疼痛和阿片类药物成瘾每个产生伏隔核的功能异常 （NAC），包括多巴胺（DA）定义，这可能归因于腹侧段的细胞发射减少 投射到NAC的区域（VTA）DA神经元。 NAC介导了滥用药物的急性奖励作用 通过MesoAccumbens途径（VTA至NAC），代表一个功能性终端，用于上升伤害感受器 途径。但是，关于慢性疼痛和有限/升级的知识，我们的知识仍然存在差距 Opioid使用相互作用以改变NAC神经元兴奋，药物摄入和疼痛敏感性。这个项目的目的 是检查慢性疼痛和阿片类药物依赖性的重叠脑生化机制 这两种疾病的担忧和潜在相互依存的贡献。我们的中心假设是 慢性疼痛诱导中唇多巴胺能信号定义驱动处方OID的发展 （即，芬太尼）滥用和芬太尼摄入量夸大了慢性炎症性疼痛的大鼠疼痛状结局。 在这里，我们建议我）慢性炎症性疼痛会增加芬太尼的摄入量，而芬太尼摄入量则夸大了 患有慢性炎症性疼痛的大鼠的痛觉过敏，ii）慢性炎症性疼痛和芬太尼摄入 增加NAC神经元和兴奋性传播到NAC神经元的内在刺激性，iii）VTA- NAC DA电路激活和/或D2样受体激动剂治疗每种都会减少痛苦并升级 患有慢性炎症性疼痛的大鼠芬太尼摄入量。这些假设反映了此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，以比较 慢性炎性疼痛态对NAC神经元电生理特性和行为的影响 定义（芬太尼摄入/动机，伤害感受），在芬太尼和短暂的途径（LGA; 12小时）中定义 进入芬太尼（SHA; 1小时）。最后，我们将使用化学遗传学和靶向药物治疗来测试 VTA-NAC DA电路激活和D2样受体激动剂对芬太尼摄入/动机的影响 患有慢性炎症性疼痛的大鼠的伤害性测量。这些研究得出的结论将有 疼痛管理和成瘾领域的重要影响，并提供潜力 VA种群的药物治疗策略患有慢性疼痛和阿片类药物成瘾。此外， 该CDA提案的一个重要特征是为申请人提供必要的关键技能培训 为了实现她成为痛苦领域的独立生物医学研究人员和领导者的长期目标 和阿片类药物成瘾研究。职业发展里程碑和轨迹将指导她的发展 独立的VA研究职业，包括行为，外科手术的过渡到独立性的过渡 电生理，药物和化学遗传技术以及对专业的关注 技能发展。总而言之，该CDA奖将极大地支持申请人向独立的过渡 VA研究地位将继续对慢性疼痛和 阿片类药物成瘾。