Opioid Modulation of the Coeruleo-Cortical Pathway

阿片类药物对蓝皮层通路的调节

• 批准号: 8050183
• 负责人: ELISABETH J VAN BOCKSTAELE
• 金额: $ 41.01万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-30 至 2013-06-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8050183
• 关键词: Agonist; Amygdaloid structure; Antihypertensive Agents; Attention; Behavior; Behavioral; Cell Nucleus; Chronic; Clinical; Complement; Confocal Microscopy; Corticotropin-Releasing Hormone; Data; Dimensions; Dose; Drug abuse; Dynorphins; Enkephalins; Excitatory Amino Acids; Frequencies; Funding; Gene Expression; Glutamates; Goals; Hippocampus (Brain); Immediate-Early Genes; Immunoelectron Microscopy; Immunohistochemistry; Individual; Infusion procedures; Ligands; Link; Maintenance; Mediating; Mental disorders; Microdialysis; Modeling; Monitor; Morphine; Neurons; Norepinephrine; Opiates; Opioid; Opioid Receptor; Pathway interactions; Pharmacodynamics; Physiological; Play; Presynaptic Terminals; Prosencephalon; Public Health; Recording of previous events; Regulation; Relapse; Relative (related person); Reporting; Research; Research Personnel; Risk Factors; Role; Site; Source; Stimulus; Stress; System; Translating; Work; biological adaptation to stress; design; endogenous opioids; frontal lobe; improved; in vivo; interest; kappa opioid receptors; light microscopy; locus ceruleus structure; norepinephrine system; novel; opioid abuse; presynaptic; programs; research study; response; sciatic nerve; stressor

DESCRIPTION (provided by applicant): The interaction between the stress axis and endogenous opioid systems has gained substantial clinical interest as it is increasingly recognized that stress predisposes to opiate abuse. For example, stress has been implicated as a risk factor in vulnerability to the initiation and maintenance of opiate abuse and is thought to play an important role in relapse in subjects with a history of abuse. However, the impact of stress-opioid interactions extends beyond vulnerability to opiate abuse. Numerous reports indicating that stress alters individual sensitivity to opiates suggest that prior stress can influence the pharmacodynamics of opiates that are used in clinical settings. Conversely, the effects of opiates on different components of the stress axis can impact on individual responsivity to stressors and potentially predispose individuals to stress- related psychiatric disorders. Because these interactions have potentially widespread clinical consequences, it is important to identify substrates of the stress response and endogenous opioid systems that interact and the specific points at which stress circuits and endogenous opioid systems intersect. During the previous funding period, we generated anatomical and physiological evidence that the locus coeruleus (LC)-norepinephrine (NE) system is reciprocally regulated by endogenous opioids and corticotropin-releasing factor (CRF). It was also demonstrated that chronic morphine sensitized the LC-NE system to CRF and stress, providing a potential mechanism that could link opiate use and vulnerability to stress-related psychiatric disorders. Importantly, new evidence was obtained for novel presynaptic actions of kappa-opioids on LC afferents, thus adding another dimension to our model of how this central NE system is co-regulated by opioids and CRF. Our general goals in this competing renewal application are to 1) identify neuroanatomical substrates for glutamate-opioid and CRF-opioid interactions that impact on the function of the LC-NE system, 2) characterize kappa-opioid receptor mediated regulation of LC spontaneous activity and afferent evoked activity, 3) characterize the impact of kappa-opioid receptor modulation of the LC on forebrain NE efflux and a behavioral endpoint of attention. This research will enhance our understanding of the interactions between stress and drug abuse and contribute to improving public health.

描述（由申请人提供）：压力轴和内源性阿片系统之间的相互作用已经获得了大量的临床兴趣，因为越来越多的人认识到压力易导致阿片类药物滥用。例如，压力被认为是易开始和维持阿片类药物滥用的风险因素，并被认为在有滥用史的受试者的复发中起重要作用。然而，压力-阿片类药物相互作用的影响超出了对阿片类药物滥用的脆弱性。许多报告表明，压力会改变个体对阿片类药物的敏感性，这表明先前的压力会影响临床环境中使用的阿片类药物的药效学。相反，阿片类药物对压力轴不同组成部分的影响可能会影响个体对压力源的反应，并可能使个体易患与压力相关的精神疾病。由于这些相互作用具有潜在的广泛的临床后果，因此重要的是要确定相互作用的应激反应和内源性阿片系统的底物以及应激回路和内源性阿片系统相交的特定点。在上一个资助期间，我们产生了解剖学和生理学证据，蓝斑（LC）-去甲肾上腺素（NE）系统是由内源性阿片类药物和促肾上腺皮质激素释放因子（CRF）调节的。研究还表明，慢性吗啡使LC-NE系统对CRF和应激敏感，提供了一种可能将阿片类药物使用和脆弱性与应激相关的精神障碍联系起来的潜在机制。重要的是，新的证据获得了新的突触前作用的κ-阿片类药物对LC传入，从而增加了另一个维度，我们的模型，这个中央NE系统是如何共同调节阿片类药物和CRF。我们在这一竞争性更新申请中的总体目标是：1）确定影响LC-NE系统功能的谷氨酸-阿片和CRF-阿片相互作用的神经解剖学底物，2）表征κ-阿片受体介导的LC自发活动和传入诱发活动的调节，3）表征LC的κ-阿片受体调节对前脑NE流出和注意力行为终点的影响。这项研究将提高我们对压力和药物滥用之间相互作用的理解，并有助于改善公众健康。