Neuronal Mechanisms of Opioid Action

描述(申请人提供)：去甲肾上腺素能蓝斑(LC)富含阿片受体，是研究阿片类药物作用神经机制的有用模型。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。我们的电生理学研究表明，除了众所周知的抑制效应外，单剂量吗啡还能在LC中诱导长时间的同步振荡放电(朱和周，2001)。这种吗啡诱导的LC同步活动可能在阿片成瘾的形成中有重要意义。作为LC同步放电的结果，吗啡可能促进接受去甲肾上腺素能LC输入的广泛脑区神经递质去甲肾上腺素(NE)的释放。NE是一种重要的神经调节剂，已被证明在几个大脑区域诱导和促进突触可塑性。我们认为，吗啡诱导的LC中的同步活动是诱导关键靶区突触可塑性的重要神经元信号，而关键靶区与阿片成瘾有关。 这一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。这种应用的一个独特的优点是，我们使用了一种多电极记录技术，允许我们同时记录多个神经元，以便研究LC神经元活动之间的时间关系。提出了三个具体目标。具体目标1将进一步描述在活体大鼠模型中吗啡诱导的LC中同步振荡放电的特征。急性和重复给药吗啡对LC同步活动的影响将被检测。具体目标2将确定吗啡诱导LC同步活动的具体机制。我们将研究LC神经元之间的电紧张性耦合的作用，以及兴奋性突触输入在吗啡诱导的LC同步化中的作用。具体目标3将研究LC输入在吗啡诱导的海马齿状回突触可塑性中的作用，海马齿状回是LC的靶区，被认为与阿片成瘾有关。这些实验将提高我们对阿片类药物作用的神经元机制的理解，这对于理解甚至治疗阿片成瘾至关重要。

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.