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

项目摘要/摘要 慢性压力与一系列疾病并存，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。其作用机制 压力是如何加剧疼痛的，以及这些机制是如何促进神经系统病理的 人们对此知之甚少。这项建议的最终目标是纠正这一不足。 在这一应用中，我们研究了臂旁外侧区的内感和躯体痛输入是如何相互作用的。 (PBL)影响疼痛行为反应的回路。我们关注儿茶酚胺能的内感传入。 有孤束尾侧内侧核(NTS)的神经元，因为这些神经元起着关键作用 在促进对压力和情绪刺激的行为反应方面的作用。我们假设慢性压力 增强儿茶酚胺能NTS(NTScat)对PBL的输入并放大PBL内的伤害性信号， 从而增强对疼痛的行为反应。我们提出三个目标： 目的1：伤害性刺激激活幼稚动物的NTScatèPBL环路。我们预测：(1)有害 刺激增强NTScat神经元活性；(1B)NTScat神经元的光遗传激活导致NA释放 以及(1C)NTScat神经元的可逆失活导致PBL中NA的释放减少 有害的刺激。 目的2：慢性应激改变PBL NTScat终末NA释放动力学。在一个动物模型中 我们预测慢性应激：(2A)伤害性刺激引起的外周血淋巴细胞NA释放被慢性应激增强； (2B)慢性应激增强了PBL神经元对伤害性刺激的反应；NTScat的失活输入到 PBL减弱这些反应；和(2C)抑制NTScat对PBL的输入可减弱慢性 对疼痛相关行为的压力。 目的3：NTScat终末释放的NA在突触前调节感觉性和情感性痛觉传入PBL和 增加了它的兴奋性。我们预测从NTScat传入释放的NA：(3A)具有延长的便捷性 对外周血淋巴细胞自发突触活动的影响；(3B)抑制中央核的抑制性传入 杏仁核到PBL；和(3C)促进从背角浅层传入到PBL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.