Opioid control of midline thalamo-cortico-striatal glutamate transmission

项目摘要 阿片类药物，如吗啡，在缓解疼痛方面有效，但也可能使人上瘾，因为它们有回报 属性。包括丘脑内侧和前部、前额叶和前扣带回在内的脑区 大脑皮层、背内侧纹状体和伏隔核参与情感和动机。 痛觉的各个方面。皮质和丘脑区的投射汇聚在纹状体上，提供 边缘系统和基底节的兴奋性神经支配的两个重要来源。这项提案将使用 基于病毒的基因传递在丘脑和大脑皮层区域表达光门离子通道实现 丘脑-纹状体和皮质-纹状体谷氨酸传入在大鼠背内侧纹状体的选择性兴奋 老鼠。全细胞记录将用于脑片，目的是了解位置和 阿片受体在这条内侧痛通路中的作用机制。 第一个目标将解决μ-阿片受体(MOPR)在这些途径中的位置。假设是这样的 阿片类药物的主要作用是通过抑制丘脑向纹状体和皮质的投射。 突触前机制，而皮质-纹状体投射对阿片类药物不敏感。 目的探讨临床相关阿片类药物吗啡慢性治疗的疗效。 芬太尼。这些激动剂在疗效和诱导MOPr磷酸化方面有很大差异。近期 研究明确地表明，MOPr的磷酸化在运输和功能测量中发挥作用 在突触后，但尚不清楚磷酸化如何或是否影响突触前功能。野生型小鼠和 一种新产生的表达磷酸化缺陷MOPr的敲入小鼠将急性和慢性 使用吗啡和芬太尼治疗，假设药物诱导的MOPr磷酸化将 导致阿片受体依赖抑制丘脑的效率降低 慢性阿片类药物治疗后谷氨酸释放(受体耐受)。磷酸化- 因此，MOPr缺陷小鼠比野生型小鼠表现出更少的受体耐受性。 这些结果将描述MOPr在这些丘脑-皮质-纹状体中的位置和作用。 并确定慢性阿片类药物治疗引起的受体和细胞水平的适应。一个 对这一环路的更好理解可能会导致更好地管理 治疗疼痛和阿片类药物的限量强化和奖励特性。

Project Summary Opioids such as morphine are effective at relieving pain but can also be addictive due to their rewarding properties. Brain areas that include the medial and anterior thalamus, prefrontal and anterior cingulate cortices, and the dorsomedial striatum and nucleus accumbens are involved in the affective and motivational aspects of pain perception. Projections from cortical and thalamic regions converge on the striatum providing two important sources of excitatory innervation to the limbic system and basal ganglia. This proposal will use viral based gene delivery to express light-gated ion channels in thalamic and cortical brain regions to achieve selective excitation of thalamo-striatal and cortico-striatal glutamate afferents in the dorsomedial striatum of mice. Whole cell recordings will be used in brain slices with the goal of understanding the location and mechanism of opioid receptor action within this medial pain pathway. The first aim will address the location of μ-opioid receptors (MOPr) in these pathways. The hypothesis is that the major effect of opioids is to inhibit thalamic projections to the striatum and cortex through a presynaptic mechanism while the cortico-striatal projections are insensitive to opioids. Aim 2 will investigate the effect of chronic treatment with the clinically relevant opioids morphine and fentanyl. These agonists differ substantially in efficacy and the induction of MOPr phosphorylation. Recent work shows definitively that phosphorylation of MOPr plays a role in trafficking and function measured postsynaptically but it is not known how or if phosphorylation affects presynaptic function. Wild-type mice and a newly generated knock-in mouse expressing phosphorylation-deficient MOPr will be acutely and chronically treated with morphine and fentanyl with the hypothesis that drug-induced MOPr phosphorylation will lead to a decrease in the efficiency of opioid receptor dependent inhibition of thalamic glutamate release (receptor tolerance) following chronic opioid treatment. The phosphorylation- deficient MOPr mouse is therefore expected to show less receptor tolerance than wild type mice. The results from these aims will describe the location and action of MOPr within these thalamo-cortico-striatal circuits and determine the receptor- and cellular-level adaptations that result from chronic opioid treatment. A better understanding of this circuitry may lead to approaches or treatment regimens that better manage the treatment of pain and limit reinforcing and rewarding properties of opioids.