Neuronal Mechanisms of Opioid Action

阿片类药物作用的神经机制

• 批准号: 6741496
• 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 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6741496
• 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（由申请方提供）：去甲肾上腺素能蓝斑（LC）富含阿片受体，是研究阿片作用神经机制的有用模型。最近，我们发现了一个新的影响吗啡，一个经典的阿片类药物，对LC神经元的放电模式。我们的电生理学研究表明，单剂量的吗啡除了其众所周知的抑制作用外，还在LC中诱导持久的同步振荡放电（Zhu和Zhou，2001）。这种吗啡诱导的LC同步活动可能在阿片类药物成瘾的发展中具有重要意义。作为同步LC放电的结果，吗啡可以促进接受去甲肾上腺素能LC输入的广泛脑区中神经递质去甲肾上腺素（NE）的释放。NE是一种重要的神经调质，已被证明可以诱导和促进多个脑区的突触可塑性。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，诱导关键靶区的突触可塑性，这是已知的阿片类药物成瘾。 该应用将更深入地研究吗啡在LC中诱导的同步活动及其对LC靶区的影响。这个应用程序的一个独特的优势是，我们采用了多电极记录技术，使我们能够同时记录几个神经元，使LC神经元的活动之间的时间关系可以研究。提出了三个具体目标。具体目标1将进一步表征在体内大鼠模型中LC中吗啡诱导的同步振荡放电。将检查急性和重复给予吗啡对LC中同步活动的影响。具体目标2将确定具体机制的吗啡诱导的同步活动的LC。我们将研究LC神经元之间的电紧张耦合的作用和兴奋性突触输入在吗啡诱导的LC同步的作用。具体目标3将研究LC输入在海马齿状回中吗啡诱导的突触可塑性中的作用，海马齿状回是被认为与阿片成瘾有关的LC靶区域。这些实验将提高我们对阿片类药物作用的神经机制的理解，这对于理解和治疗阿片类药物成瘾至关重要。