The Role of Mesoaccumbens Dopamine in Pain and Prescription Opioid Addiction

退伍军人事务职业发展奖(CDA)-2将为学术职业发展提供支持 通过有指导的研究和专业技能发展为过渡到学术 研究型教师的职位。建议的活动将在尼古拉斯·吉尔平博士的指导下进行 Zadina、Scott Edwards和Tiffany Wills，并将促进假设驱动的研究和独立 调查。慢性疼痛影响着1亿美国成年人，每年给国家造成约6350亿美元的损失 医疗成本和生产力损失。由于退伍军人中慢性疼痛的高患病率， 治疗慢性疼痛是退伍军人事务部(VA)的首要任务，处方阿片类药物是 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 慢性疼痛可能容易发展成阿片成瘾和/或使用非法阿片类药物自我治疗疼痛 症状。慢性疼痛和阿片成瘾均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 向NAC投射的VTA区DA神经元。NAC调节滥用药物的急性奖赏效应 通过系膜伏隔通路(VTA至NAC)，代表了上行伤害性感受的功能终末 小路。然而，我们对慢性疼痛和有限/升级的认识仍然存在差距。 阿片类药物的使用相互作用，改变NAC神经元的兴奋性、药物摄入量和疼痛敏感性。这个项目的目的是 是检查慢性疼痛和阿片类药物依赖的重叠的大脑生化机制，这可能 导致这两种疾病的恶化和潜在的相互依存。我们的中心假设是 慢性疼痛导致中脑边缘多巴胺能信号缺陷，从而推动处方阿片类药物的发展 (即，芬太尼)滥用和芬太尼摄入会夸大患有慢性炎症性疼痛的大鼠的痛样结果。 在这里，我们提出：1)慢性炎症性疼痛增加了芬太尼的摄入量，而芬太尼的摄入量夸大了 慢性炎症性疼痛大鼠的痛敏反应，II)慢性炎症性疼痛和芬太尼摄入 增加NAC神经元的内源性兴奋性和向NAC神经元的兴奋性传递，以及III)VTA- NAC DA通路激活和/或D2样受体激动剂治疗均可减轻痛觉过敏并使痛觉过敏升级 芬太尼在慢性炎症性疼痛大鼠中的应用。这些假设反映了本CDA中目标的顺序 求婚。为了研究这些假设，我们提出了一种创新的实验策略，将 慢性炎症性疼痛状态对NAC神经元电生理特性和行为学的影响 给予长时间使用芬太尼和短时间使用芬太尼的动物的缺陷(芬太尼摄取/动力、伤害感) 芬太尼(Sa；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环路激活和D2样受体激动剂对芬太尼摄取/动力和血压的影响 慢性炎症性疼痛大鼠的伤害性措施。这些研究得出的结论将会有 在疼痛管理和成瘾领域产生重要影响，并提供潜力 退伍军人管理局慢性疼痛和阿片成瘾患者的药物治疗策略。此外, CDA提案的一个重要特点是为申请者提供必要的关键技能培训 实现她成为一名独立的生物医学研究人员和疼痛领域的领导者的长期目标 以及阿片成瘾研究。职业发展的里程碑和轨迹将指导她的进步 独立的退伍军人研究生涯，包括在行为、外科、 电生理学、药理学和化学遗传学技术，以及对专业人员的关键关注 技能发展。总而言之，这个CDA奖项将极大地促进申请者向独立的 VA研究立场，继续未来研究慢性疼痛的生物行为机制 阿片成瘾。

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.