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.

催产素在多种疼痛状态下会产生啮齿动物的抗伤害感受，但是 发生这种情况的机制以及外围和中心效应的重要性是 不清楚。先前的研究通常使用全身施用催产素，并进行剂量至 在没有药代动力学数据或考虑大脑渗透率的情况下实现策略。 这些研究只能在相关给药参数之后推断到诊所 通过实验确定以实现啮齿动物的外围和中央催产素的暴露 和人类，并使用此类参数将抗伤害感受功效与不同的不同 结果指标，随后探索潜在机制。这个项目 翻译并由项目1和3告知，以定义催产素的药代动力学 在大脑和血液中醒着和麻醉大鼠，并确定外周的相关性 催产素对神经损伤后复杂行为的中心作用。三个具体目标是 建议的。第一个目的将使用血浆和大脑中催产素的药代动力学使用 I.V.推注，这些数据将用于设计目标浓度输注范例 PK/PD核心。还将评估大脑进入和损失的速度。第二个目标将采取 我们组开发的新型转基因大鼠的优势表达了CRE重组酶 有选择地在催产毒素能神经元中。我们将确定内源性催产素回路的作用 在外周神经损伤后使用CRE依赖性神经元调节复杂行为 消融策略，表达靶向神经元中突变的caspase 3。我们已经发展了 评估注意力障碍，避免恐惧和情感的新型行为方法 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2的知识来评估 催产素在减轻周围神经损伤引起的行为变化中的功效， 测试催产素对行为产生持久的疾病改良作用的潜力 和传入的生理学，以及内源性回路在这些作用中的作用。这个项目 与项目1相互作用，以评估改变的主要感觉传递信号的贡献 复杂的行为以及催产素的相关性以及与项目3的相关外围的相关性 人类中的催产素水平用于外围和中央作用。