Chronic Pain Modulation of Mesolimbic Dopamine Signaling for Natural and Opiate Rewards

项目摘要/摘要 慢性疼痛是一种使人衰弱的疾病，会导致长期残疾。慢性疼痛引发负面情绪 经常导致焦虑反省和情绪低落的状态，患者不得不不断地 在减少痛苦但限制日常生活的行为之间做出选择，还是坚持忍受痛苦。当前 慢性疼痛的治疗通常涉及处方阿片类药物。虽然处方阿片类药物提供了急需的 除了止痛，阿片类药物也有很高的滥用潜力，使患者有发展成阿片成瘾的风险。 慢性疼痛引起的动机-情感变化表明，这种衰弱的状况本身可能 增加阿片成瘾的风险。慢性疼痛和情感障碍表现为核内功能障碍 伏隔核(CNAC)，大脑奖赏回路中的一个区域，接受来自 腹侧被盖区(VTA)，在线索-奖赏关联的动机和学习中起着重要作用。我 假设慢性疼痛(1)通过多巴胺的变化增加阿片类药物的成瘾潜力 信号传递增加了习得的积极线索联想的强度，以及(2)增加了获得的动机 阿片类药物奖励。在这项提案中，我将测试学习到的积极线索联想和激励努力如何 获得阿片类药物奖励会因疼痛而改变。在目标1中，我将使用神经病理性疼痛动物模型，巴甫洛夫 调节蔗糖奖励，体内纤维光度法测试未经治疗的急性和慢性的效果 VTA到CNAC的疼痛在灭绝和恢复期间传递多巴胺信号以获得食物奖励。在《目标2》中，我会 将相同的疼痛模型与体内纤维光度法结合使用，以检查慢性疼痛的变化 在阿片类药物奖励的可操作性任务中，VTA向CNAC传递多巴胺信号。这些实验的结果将 帮助确定疼痛和阿片成瘾之间的行为和神经生物学相互作用。我的提议， 根据NIDA的目标，将有助于确定生物和行为原因，并 终生使用毒品和成瘾的后果。根据这笔培训补助金，我计划接受培训 口头交流、教学、助学金和手稿写作、编程以及对药物的进一步了解 虐待和上瘾。我过去的经历，我现在的训练计划，以及我的指导团队，使我成为 获得NRSA证书的理想人选。我打算利用这笔赠款提供的机会和培训来 成为一名有竞争力的博士后研究员，并最终成为一名成功的文科独立研究员 少数群体服务机构。

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.