Stress-induced plasticity in noradrenergic analgesia

项目摘要 本研究的总体目标是更好地了解中枢去甲肾上腺素能的镇痛特性。 系统。面对身体伤害和心理创伤时的情绪调节是长期的关键 生存和生活质量。无法控制的焦虑、快感缺乏和抑郁通常会导致以下时期 长期的压力或慢性疼痛。慢性疼痛和压力都会导致重叠的生理适应 使得相同的三环和5-羟色胺/去甲肾上腺素再摄取抑制剂(SNRI)被开发并用于 治疗抑郁症在治疗慢性疼痛方面也很有效。因此，去甲肾上腺素(NE)可能是 调节应激过程中疼痛处理的关键神经递质。在这项提案中，我们试图定义 NE在应激诱导的疼痛调节中的作用。蓝斑-去甲肾上腺素(LC-NE)系统是一个特殊的系统 中枢神经系统靶点，有望同时干预慢性疼痛和应激诱导 精神障碍。本研究的重点在于了解LC-NE系统 调节内源性止痛以及慢性应激如何影响这一系统。这一点的中心假设是 认为LC-NE神经元活动在应激诱导的伤害性感受调制中起关键作用。的第一个目标 这项建议将在体内评估LC-NE神经元在急性应激诱导的抗伤害感受中的作用。 光遗传学和化学遗传学。第二个目标是试图了解从 急性应激诱导的对慢性应激诱导的原伤害性感觉的抗伤害作用。特别是，这一目标寻求 确定重复应激刺激LC-NE是否会驱动应激诱导 原伤害性感觉。为此，我们将使用体内光遗传学、化学遗传学和交叉遗传学 反复束缚应激时去除LC-NE功能的模型。最终的目标是澄清两个 研究慢性应激的不同模型揭示了与疼痛相关的相反的表型。这里，我们将使用Brain 切片电生理和体内纤维光度法监测这些应激模式下的LC-NE活性 以及对有害刺激的反应。这些实验加在一起，将产生以前无法实现的 关于LC-NE神经元和相关的传出电路的信息，这些传出电路调节大鼠的痛相关行为 对压力源的反应。这些研究将确定LC-NE系统的作用：1)在急性应激诱导 止痛，2)向慢性应激引起的痛觉过敏的转变，以及3)确定其机制 不同形式的应激改变了LC-NE的功能和伤害性感受。此信息对于翻译将非常重要 针对去甲肾上腺素系统治疗疼痛和神经精神障碍的研究。

Project Summary The overall goal of this research is to better understand the analgesic properties of central noradrenergic systems. Emotional regulation in the face of physical injury and psychological trauma is critical to long-term survival and quality of life. Uncontrollable anxiety, anhedonia, and depression often result following periods of prolonged stress or chronic pain. Both chronic pain and stress lead to overlapping physiological adaptations such that the same tricyclic and serotonin/norepinephrine reuptake inhibitors (SNRIs) developed and used to treat depression are also effective in treating chronic pain. Therefore, norepinephrine (NE) is likely one of the key neurotransmitters regulating pain processing during stress. In this proposal we seek to define the role of NE in stress-induced modification of pain. The locus coeruleus-noradrenergic (LC-NE) system is one particular central nervous system target that holds promise for interventions in both chronic pain and stress-induced psychiatric disorders. This research focuses on understanding the mechanisms by which the LC-NE system modulates endogenous analgesia and how chronic stress affects this system. The central hypothesis of this proposal is that LC-NE neuronal activity is critical for stress-induced modulation of nociception. The first aim of this proposal will assess the role of LC-NE neurons in acute stress-induced antinociception using in vivo optogenetics and chemogenetics. The second aim seeks to understand the mechanism for the transition from acute stress-induced antinociception to chronic stress-induced pronociception. In particular, this aim seeks to determine whether repeated LC-NE stimulation from repeated stress exposure drives stress-induced pronociception. To do so we will use, using in vivo optogenetics, chemogenetics, and intersectional genetic models to remove LC-NE function during repeated restraint stress. The final aim seeks to clarify how two different models for studying chronic stress reveal opposing pain-related phenotypes. Here, we will use brain slice electrophysiology and in vivo fiber photometry to monitor LC-NE activity following these stress paradigms and in response to noxious stimuli. Together these experiments will generate previously unattainable information about LC-NE neurons and associated efferent circuitry that regulate the pain-related behaviors in response to stressors. These studies will define the role of the LC-NE system; 1) in acute stress-induced analgesia, 2) the transition to chronic stress-induced hyperalgesia, and 3) identify mechanisms by which different forms of stress alter LC-NE function and nociception. This information will be critical for translational research targeting the noradrenergic system in the treatment of pain and neuropsychiatric disorders.