The Role of Mesoaccumbens Dopamine in Pain and Prescription Opioid Addiction

这个退伍军人事务职业发展奖（CDA）-2将提供学术职业发展的支持 通过指导研究和专业技能发展，为过渡到学术 研究员职位。拟议的活动将在Nicholas Gilpin博士的指导下进行，James Zadina，Scott Edwards和Tiffany Wills将促进假设驱动的研究和独立的研究。 调查慢性疼痛影响超过1亿美国成年人，每年花费约6350亿美元。 医疗费用和生产力损失。由于退伍军人中慢性疼痛的高发率， 慢性疼痛的治疗是退伍军人事务部（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，退伍军人长期接受阿片类药物治疗， 慢性疼痛可能易受阿片类药物成瘾和/或使用非法阿片类药物自我抑制疼痛的影响 症状慢性疼痛和阿片类药物成瘾各自都会导致丘脑核的功能异常 (NAc)包括多巴胺（DA）缺陷，这可能是由于腹侧被盖细胞放电减少 腹侧被盖区（VTA）DA能神经元投射到NAc。NAc介导药物滥用的急性奖赏效应 通过mesoadrenbens途径（VTA至NAc），并代表上行伤害感受的功能性末端 途径。然而，我们对慢性疼痛和有限/升级的认知仍然存在差距。 阿片类药物的使用相互作用改变NAc神经元兴奋性、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的重叠脑生化机制， 导致这两种疾病的恶化和潜在的相互依赖。我们的核心假设是 慢性疼痛诱导中脑边缘多巴胺能信号传导缺陷，从而驱动处方阿片类药物的开发 (i.e.,芬太尼）滥用，芬太尼摄入量夸大了慢性炎性疼痛大鼠的疼痛样结果。 在这里，我们提出，I）慢性炎性疼痛增加芬太尼的摄入量，芬太尼的摄入量夸大了 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， 增加NAc神经元的内在兴奋性和兴奋性传递到NAc神经元，和III）VTA- NAc DA回路激活和/或D2样受体激动剂治疗各自减少痛觉过敏并使其升高。 芬太尼摄入对慢性炎症性疼痛大鼠的影响。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，我们提出了一个创新的实验策略，比较了 慢性炎性疼痛状态对NAc神经元电生理特性和行为的影响 在给予长时间（LgA; 12小时）芬太尼和短时间（LgA; 12小时）芬太尼的动物中， 进入（ShA; 1小时）芬太尼。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回路激活和D2样受体激动对芬太尼摄入/动机和 慢性炎性疼痛大鼠的伤害性测量。这些研究得出的结论将具有 在疼痛管理和成瘾领域的重要影响，以及提供潜在的 为患有慢性疼痛和阿片类药物成瘾的VA人群提供药物治疗策略。此外，本发明还提供了一种方法， 该CDA建议书的一个重要特点是，为申请人提供必要的关键技能培训 以实现她的长期目标，成为一名独立的生物医学研究人员和疼痛领域的领导者 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研究生涯，包括在行为，手术， 电生理学，药理学和化学遗传学技术，以及对专业的关键重点 技能发展。总之，这个CDA奖将大大促进申请人的过渡到一个独立的 VA研究的立场，继续未来的调查慢性疼痛的生物行为机制， 阿片类药物成瘾

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.