Opioid Modulation of the Coeruleo-Cortical Pathway

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，因为人们越来越认识到压力容易导致阿片类药物滥用。例如，压力已被认为是易于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成分的影响可以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临床后果，因此确定应激反应和内源性阿片系统相互作用的底物以及应激回路和内源性阿片系统相交的具体点是很重要的。在之前的资助期内，我们获得了解剖学和生理学证据，证明蓝斑(LC)-去甲肾上腺素（NE）系统受内源性阿片和促肾上腺皮质激素释放因子（CRF）的相互调节。研究还表明，慢性吗啡使LC-NE系统对CRF和应激敏感，这为阿片类药物使用与应激相关精神疾病易感性之间的联系提供了一种潜在机制。重要的是，我们获得了新的证据，证明kappa-阿片样物质对LC事件的突触前作用，从而为我们的模型增加了阿片样物质和CRF如何共同调节中枢NE系统的另一个维度。我们在这一竞争性更新应用中的总体目标是：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基础；2)表征kappa-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kappa-阿片受体调节LC对前脑NE外排和注意行为终点的影响。这项研究将加强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。

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.