Central oxytocin mechanisms of pain recovery following nerve injury

催产素在各种疼痛状态的啮齿动物中产生抗伤害性感觉，然而 发生这种情况的机制以及外围效应与中枢效应的重要性是 不清楚。以前的研究通常使用催产素的全身给药，剂量到- 在缺乏药代动力学数据或考虑脑外显率的情况下的效果策略。 这些研究只有在相关的剂量参数被确定之后才能外推到临床。 通过实验确定在啮齿动物中实现外周和中枢催产素暴露 和人类，并使用这些参数来比较不同 结果衡量，并随后探索可能的机制。本项目 翻译项目1和项目3以定义催产素的药代动力学 清醒和麻醉大鼠的脑和血液中，并确定外周血和 催产素在神经损伤后复杂行为中的中枢作用。三个具体目标是 建议。第一个目标是确定催产素在血浆和脑中的药代动力学。 静脉注射。这些数据将被用来设计靶向浓度输注范例 PK/PD核心。还将评估大脑进入和丧失的比率。第二个目标将采取 本课题组研制的新型表达Cre重组酶转基因大鼠的优势 选择性地存在于催产素能神经元中。我们将确定内源性催产素回路的作用 CRE依赖神经元对周围神经损伤后复杂行为的调节作用 消融策略，在靶神经元中表达突变的caspase3。我们已经开发出 新的行为方法，评估注意力受损，恐惧回避和情感和 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。第三个目标结合了从目标1和目标2获得的知识，以评估 催产素减轻周围神经损伤所致行为改变的疗效 测试催产素在行为中产生持久的、改善疾病的效果的可能性 以及传入生理学，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在脑内的作用 复杂行为与催产素和项目3靶向相关外周的相关性 人类外周和中枢活动的催产素水平。

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.