Central oxytocin mechanisms of pain recovery following nerve injury

神经损伤后疼痛恢复的中枢催产素机制

• 批准号: 10332264
• 负责人: THOMAS JEFFREY MARTIN
• 金额: $ 33.3万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-15 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10332264
• 关键词: Ablation; Affective; Amygdaloid structure; Analgesics; Animal Model; Animals; Attention; Behavior; Behavioral; Blood; Bolus Infusion; Brain; CASP3 gene; Clinic; Cognitive; Complex; Computers; Data; Disease; Dose; Drug Kinetics; Engineering; Enterobacteria phage P1 Cre recombinase; Exposure to; Female; Fright; Human; Impaired cognition; Impairment; Infusion procedures; Injections; Injury; Knowledge; Lead; Literature; Methods; Modality; Modeling; Movement; Mutate; Nervous system structure; Neurons; Nociception; Outcome Measure; Oxytocin; Oxytocin Receptor; Pain; Pain management; Pathway interactions; Penetrance; Perioperative; Peripheral; Peripheral nerve injury; Persistent pain; Physiology; Plasma; Program Research Project Grants; Rattus; Recovery; Reflex action; Resolution; Rodent; Role; Route; Sensory; Signal Transduction; Spinal; Spinal nerve structure; Surface; Testing; Time; Transgenic Organisms; Translating; Trauma; Viral; affective disturbance; antagonist; awake; behavior measurement; behavioral study; chronic pain; design; dorsal horn; experimental study; injury recovery; innovation; male; midbrain central gray substance; nerve injury; novel; pain behavior; pain chronification; pharmacokinetic model; pre-clinical; response

Oxytocin produces antinociception in rodents in a variety of pain states, however the mechanisms by which this occurs and the importance of peripheral versus central effects are unclear. Prior studies have typically used systemic administration of oxytocin, with dosing-to- effect strategies in the absence of pharmacokinetic data or consideration of brain penetrance. These studies can only be extrapolated to the clinic after relevant dosing parameters have been determined experimentally to achieve peripheral and central oxytocin exposure across rodents and humans, and using such parameters to compare antinociceptive efficacy against different outcome measures, with subsequent exploration of potential mechanisms. This Project translates and is informed by Projects 1 and 3 to define the pharmacokinetics of oxytocin in awake and anesthetized rats in brain and blood and determine the relevance of peripheral and central action of oxytocin on complex behaviors following nerve injury. Three specific aims are proposed. The first aim will define the pharmacokinetics of oxytocin in plasma and brain using i.v. bolus, and these data will be used to design targeted concentration infusion paradigms in the PK/PD core. The rate of brain entry and loss will also be assessed. The second aim will take advantage of a novel transgenic rat developed by our group that expresses Cre recombinase selectively in oxytocinergic neurons. We will determine the role of endogenous oxytocin circuits in modulation of complex behaviors after peripheral nerve injury using Cre dependent neuronal ablative strategies, expressing mutated caspase 3 in targeted neurons. We have developed novel behavioral methods that assess impairment of attention, fear avoidance, and affective and sensory modalities of pain after nerve injury and use these innovative behavioral methods for this aim. The third aim combines the knowledge gained from Aims 1 and 2 to assess the efficacy of oxytocin in mitigating the behavioral changes induced by peripheral nerve injury, tests the potential for oxytocin to produce long-lasting, disease-modifying effects in behavior and afferent physiology, and the role of endogenous circuits in these effects. This project interacts with Project 1 to assess the contribution of altered primary sensory afferent signaling in complex behaviors and the relevance of oxytocin and with Project 3 to target relevant peripheral levels of oxytocin in humans for peripheral and central action.

催产素在啮齿类动物的各种疼痛状态下产生抗伤害感受，然而， 发生这种情况的机制以及外周效应与中枢效应的重要性， 不清楚先前的研究通常使用催产素的全身给药， 在缺乏药代动力学数据或考虑脑转移的情况下， 这些研究只能在确定相关给药参数后外推至临床。 通过实验确定啮齿动物的外周和中枢催产素暴露 和人，并使用这些参数来比较针对不同的抗伤害性功效。 结果测量，随后探索潜在的机制。这个项目 翻译并由项目1和3提供信息，以定义催产素在 唤醒和麻醉大鼠的脑和血液，并确定外周和 催产素对神经损伤后复杂行为的中枢作用。三个具体目标是 提出了第一个目标将使用以下方法定义催产素在血浆和脑中的药代动力学： 静脉推注，这些数据将用于设计目标浓度输注范例， PK/PD核心还将评估脑进入和丢失率。第二个目标将采取 本研究组开发的表达Cre重组酶的新型转基因大鼠的优点 选择性地在催产素能神经元中。我们将确定内源性催产素回路的作用 Cre依赖性神经元对周围神经损伤后复杂行为的调节 消融策略，在靶向神经元中表达突变的caspase 3。我们已经开发 新的行为方法，评估注意力障碍，恐惧回避，情感和 神经损伤后疼痛的感觉方式，并使用这些创新的行为方法， 这个目标。第三个目标结合了目标1和目标2中获得的知识， 催产素减轻周围神经损伤引起的行为变化的功效， 测试催产素在行为方面产生持久的、疾病缓解效果的潜力 和传入生理学，以及内源性回路在这些效应中的作用。这个项目 与项目1相互作用，以评估改变的初级感觉传入信号的贡献， 复杂的行为和催产素的相关性，并与项目3，以目标相关的周边 催产素在人类外周和中枢作用的水平。