Neuronal Mechanisms of Opioid Action

阿片类药物作用的神经机制

• 批准号: 6606102
• 负责人: HONG ZHU
• 金额: $ 7.4万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-25 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6606102
• 关键词: drug addiction; electrophysiology; hippocampus; laboratory rat; locus coeruleus; morphine; neural plasticity; neurons; norepinephrine; opioid receptor; synapses

DESCRIPTION (provided by applicant): The noradrenergic locus coeruleus (LC) is enriched with opioid receptors and has been a useful model to study the neuronal mechanisms of opioid action. Recently, we found a novel effect of morphine, a classic opioid drug, on the firing pattern of LC neurons. Our electrophysiological studies show that a single dose of morphine induces long-lasting synchronous oscillatory discharges in the LC in addition to its well-known inhibitory effect (Zhu and Zhou, 2001). This morphine-induced synchronous activity in the LC may have important implications in the development of opioid addiction. As a result of the synchronized LC firing, morphine may facilitate the release of neurotransmitter norepinephrine (NE) in widespread brain areas that receive noradrenergic LC input. NE, an important neuromodulator, has been shown to induce and facilitate synaptic plasticity in several brain regions. We propose that the morphine-induced synchronous activity in the LC is an important neuronal signal that induces synaptic plasticity in critical target areas, which are known to contribute to opioid addiction. This application will more thoroughly study the morphine-induced synchronous activity in the LC and its influence on the LC target areas. A unique strength of this application is that we employ a multiple-electrode recording technique that allows us to record several neurons simultaneously so that the temporal relationship among the activities of LC neurons can be studied. Three specific aims are proposed. Specific Aim 1 will further characterize the morphine-induced synchronous oscillatory discharges in the LC in an in vivo rat model. Effects of acute and repeated administration of morphine on synchronous activity in the LC will be examined. Specific Aim 2 will identify the specific mechanisms underlying the morphine-induced synchronous activity in the LC. We will examine the role of electrotonic coupling among LC neurons and the role of excitatory synaptic input in the morphine-induced LC synchrony. Specific aim 3 will study the role of LC input in the morphine-induced synaptic plasticity in the dentate gyrus of the hippocampus, an LC target area thought to be involved in opioid addiction. These experiments will improve our understanding of neuronal mechanisms of opioid action, which is crucial for understanding and perhaps treating of opioid addiction.

描述（由申请人提供）：去肾上腺素能蓝斑（LC）富含阿片受体，是研究阿片作用神经元机制的有用模型。最近，我们发现了经典阿片类药物吗啡对LC神经元放电模式的新影响。我们的电生理研究表明，单剂量吗啡除了其众所周知的抑制作用外，还会在LC中诱发持久的同步振荡放电（Zhu和Zhou， 2001）。吗啡诱导的LC同步活动可能在阿片成瘾的发展中具有重要意义。作为同步LC放电的结果，吗啡可能促进神经递质去甲肾上腺素（NE）在接受去甲肾上腺素能LC输入的广泛脑区释放。NE是一种重要的神经调节剂，已被证明可以诱导和促进大脑多个区域的突触可塑性。我们认为吗啡诱导的LC同步活动是一个重要的神经元信号，可以诱导关键靶区的突触可塑性，从而导致阿片类药物成瘾。