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

内感受和疼痛：臂旁核伤害感受传递的去甲肾上腺素能调节

• 批准号: 10655093
• 负责人: Nathan P Cramer
• 金额: $ 49.21万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10655093
• 关键词: Affect; Affective; Amygdaloid structure; Anatomy; Animal Model; Animals; Anxiety; Attenuated; Behavior; Cell Nucleus; Chronic; Chronic stress; Cognitive; Electrophysiology (science); Emotional; Fiber; Fright; Goals; Homeostasis; Hypothalamic structure; In Vitro; Interoception; Intervention; Lateral; Learning; Mental Depression; Nervous System; Neurons; Nociception; Nucleus solitarius; Output; Pain; Pathology; Pathway interactions; Pharmacogenetics; Photometry; Play; Positioning Attribute; Presynaptic Terminals; Prosencephalon; Quality of life; Role; Route; Sensory; Signal Transduction; Sleep disturbances; Spinal; Stimulus; Stress; Structure; Synapses; Testing; Time; Trigeminal System; Vertebral column; Visceral; Visceral Afferents; behavioral response; comorbidity; dorsal horn; emotional stimulus; in vivo; multimodality; noradrenergic; novel; optogenetics; pain signal; parabrachial nucleus; respiratory; response; restraint stress; sensor; sensory input; transmission process

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.

项目摘要/摘要 慢性压力是合并的，具有广泛的疾病，例如焦虑，抑郁，睡眠障碍， 和痛苦。慢性压力在加剧疼痛和生活质量丧失方面起着至关重要的作用。机制 压力加剧疼痛以及这些机制如何促进神经系统病理学的疼痛是 理解不佳。该提案的最终目标是纠正这种缺陷。 在此应用中，我们研究了互感和躯体疼痛输入如何在侧面瘫痪中相互作用 （PBL）电路影响对疼痛的行为反应。我们专注于儿茶酚胺能的互感输入 具有固体道（NTS）的尾形培养基核的神经元，因为这些神经元起着关键作用 在支持对压力和情绪刺激的行为反应中的作用。我们假设慢性压力 增强对PBL的Catecholamin能NTS（NTSCAT）输入PBL和放大器在PBL中的伤害感受信号， 导致对疼痛的行为反应增强。我们提出了3个目标： AIM 1：有害刺激激活幼稚动物中的NTSCATèpbl电路。我们预测：（1a）有害 刺激增强了NTSCAT神经元活性； （1B）NTSCAT神经元的光遗传激活导致Na释放 pbl; （1C）NTSCAT神经元的可逆失活导致Na在PBL中的释放减少以响应 有害刺激。 AIM 2：慢性应力改变了NTSCAT终端中Na释放的动力学。在动物模型中 我们预测的慢性应激：（2A）慢性应激增强了有害刺激引起的PBL中的Na释放； （2B）PBL神经元对有害刺激的反应通过慢性压力增强； NTSCAT输入到 PBL削弱了这些反应； （2C）抑制NTSCAT输入以减轻慢性的影响 压力与疼痛相关的行为。 AIM 3：NTSCAT终端发布的NA，突触前会调节对PBL和PBL的情感疼痛输入 增加了令人兴奋的。我们预测NA从NTSCAT传入中释放：（3A）具有延长的功能 对PBL的赞助合成活性的影响； （3B）抑制从中央核的抑制输入 杏仁核至PBL； （3C）促进了从表面背角传入的PBL神经元的兴奋性输入。