Interoception and Pain: Noradrenergic Modulation of Nociceptive Transmission in the Parabrachial Nucleus

项目总结/摘要 慢性压力与多种疾病并存，如焦虑、抑郁、睡眠障碍， 和痛苦.慢性压力在加剧疼痛和生活质量下降方面起着至关重要的作用。的机制 压力加剧疼痛的机制，以及这些机制如何导致神经系统病理学， 不太了解。本提案的最终目标是纠正这一缺陷。 在这个应用中，我们研究了内感受性和躯体疼痛输入如何在外侧臂旁神经内相互作用， (PBl)影响疼痛行为反应的神经回路。我们专注于内感受性输入从儿茶酚胺能 孤束核（NTS）的神经元，因为这些神经元起着关键的作用。 促进对压力和情绪刺激的行为反应的作用。我们假设慢性压力 增强对PB 1的儿茶酚胺能NTS（NTScat）输入并放大PB 1内的伤害性信号传导， 导致对疼痛的行为反应增强。我们提出三个目标： 目的1：在幼稚动物中，诺鲁刺激激活NTScat èPBl回路。我们预测：（1A）诺维 刺激增强NTScat神经元的活性;（1B）NTScat神经元的光遗传激活引起神经元中的NA释放。 （1C）NTScat神经元的可逆失活导致PB 1中NA的释放减少， 有害的刺激。 目的2：慢性应激改变PB 1神经元NTScat终末NA释放的动力学。的动物模型中 慢性应激可促进伤害性刺激引起的PB 1区NA释放; (2B)PB 1神经元对伤害性刺激的反应被慢性应激增强; NTScat输入的失活， （2C）抑制NTScat对PB 1的输入减弱了慢性炎症的影响。 强调疼痛相关的行为。 目的3：NTScat终末突触前释放的NA调节PB 1和PB 2的感觉和情感痛输入， 增加了它的兴奋性。我们预测NTScat传入神经元释放的NA：（3A）具有长时间的易化作用， 对PB 1中自发突触活动的影响;（3B）抑制来自PB 1中央核的抑制性输入。 （3C）促进从浅背角传入到PB 1神经元的兴奋性输入。

Project Summary/Abstract Chronic stress is comorbid with a wide spectrum of conditions, such as anxiety, depression, sleep disturbances, and pain. Chronic stress plays a crucial role in exacerbating pain and the loss of quality of life. The mechanisms by which stress exacerbate pain, and how these mechanisms contribute to nervous system pathology, are poorly understood. The ultimate goal of this proposal is to rectify this deficiency. In this application, we study how interoceptive and somatic pain inputs interact within lateral parabrachial (PBl) circuits to affect behavioral responses to pain. We focus on interoceptive inputs from catecholaminergic neurons with the caudal mediodoral nucleus of the solitary tract (NTS) because these neurons play a pivotal role in facilitating behavioral responses to stress and emotional stimuli. We Hypothesize that chronic stress potentiates catecholaminergic NTS (NTScat) inputs to PBl and amplifies nociceptive signaling within PBl, resulting in enhanced behavioral responses to pain. We propose 3 aims: Aim 1: Noxious stimuli activate the NTScat èPBl circuit in naïve animals. We predict that: (1A) Noxious stimuli enhances NTScat neuronal activity; (1B) Optogenetic activation of NTScat neurons causes NA release in PBl; and (1C) Reversible inactivation of NTScat neurons results in diminished release of NA in PBl in response to noxious stimulation. Aim 2: Chronic stress alters dynamics of NA release from NTScat terminals in PBl. In an animal model of chronic stress we predict: (2A) NA release in PBl evoked by noxious stimulation is enhanced by chronic stress; (2B) PBl neuron responses to noxious stimuli are enhanced by chronic stress; inactivation of NTScat inputs to PBl attenuates these responses; and (2C) Suppression of NTScat inputs to PBl attenuates the effects of chronic stress on pain-related behaviors. Aim 3: NA released by NTScat terminals presynaptically regulates sensory and affective pain inputs to PBl and increases its excitability. We predict that NA released from NTScat afferents: (3A) Has a prolonged faciliatory effect on spontaneous synaptic activity in PBl; (3B) Suppresses inhibitory inputs from the central nucleus of the amygdala to PBl; and (3C) Facilitates excitatory inputs to PBl neurons from superficial dorsal horn afferents.