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

项目概要/摘要 慢性压力与多种疾病共存，例如焦虑、抑郁、睡眠障碍、 和疼痛。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。机制 压力如何加剧疼痛，以及这些机制如何导致神经系统病理学， 不太了解。该提案的最终目标是纠正这一缺陷。 在此应用中，我们研究内感受和躯体疼痛输入如何在臂旁外侧神经内相互作用 (PBl)影响对疼痛的行为反应的电路。我们专注于儿茶酚胺能的内感受输入 神经元与孤束尾中核（NTS），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中发挥作用。我们假设慢性压力 增强儿茶酚胺能 NTS (NTScat) 输入到 PBl 并放大 PBl 内的伤害性信号传导， 从而增强对疼痛的行为反应。我们提出3个目标： 目标 1：有害刺激激活幼稚动物的 NTScat èPBl 回路。我们预测： (1A) 有害 刺激增强 NTScat 神经元活动； (1B) NTScat 神经元的光遗传学激活导致 NA 释放 PBl; (1C) NTScat 神经元的可逆失活导致 PBl 中 NA 的释放减少 到有害刺激。 目标 2：慢性应激改变 PBl 中 NTScat 终端释放 NA 的动态。在动物模型中 慢性应激我们预测：（2A）慢性应激会增强有害刺激引起的PBl中NA的释放； (2B)PB1神经元对有害刺激的反应因慢性应激而增强； NTScat 输入失活 PBl 减弱这些反应； (2C)抑制NTScat对PBl的输入可减弱慢性病的影响 对与疼痛相关的行为施加压力。 目标 3：NTScat 终端释放的 NA 调节突触前对 PBl 和情感疼痛的输入 增加其兴奋性。我们预测 NTScat 传入神经释放的 NA：(3A) 具有长期的促进作用 对PBl中自发突触活动的影响； (3B) 抑制来自中央核的抑制性输入 杏仁核至PBl; (3C)促进从浅表背角传入神经元到PB1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.