Opioid control of midline thalamo-cortico-striatal glutamate transmission

项目摘要 吗啡等阿片类药物可以有效缓解疼痛，但由于其奖励作用，也可能成瘾 特性.包括内侧和前丘脑、前额叶和前扣带回在内的大脑区域 皮质、背内侧纹状体和背内侧核参与了情感和动机的调节， 疼痛感知方面。来自皮质和丘脑区域的投射会聚在纹状体上， 边缘系统和基底神经节兴奋性神经支配的两个重要来源。该提案将使用 基于病毒的基因递送，以在丘脑和皮质脑区域中表达光门控离子通道， 背内侧纹状体选择性兴奋丘脑-纹状体和皮质-纹状体谷氨酸传入 小鼠全细胞记录将用于大脑切片，目的是了解大脑的位置， 阿片受体的作用机制在这个中间疼痛途径。 第一个目标将解决μ-阿片受体（MOPr）在这些通路中的位置。前提是 阿片类药物的主要作用是抑制丘脑向纹状体和皮质的投射， 突触前机制，而皮质-纹状体投射对阿片不敏感。 目的2将研究与临床相关的阿片类药物吗啡和 芬太尼这些激动剂在功效和MOPr磷酸化的诱导方面有很大不同。最近 工作明确显示MOPr的磷酸化在运输和功能测量中起作用， 但是不知道磷酸化如何或是否影响突触前功能。野生型小鼠和 新产生的表达磷酸化缺陷型MOPr的基因敲入小鼠将被急性和慢性地 用吗啡和芬太尼治疗，假设药物诱导的MOPr磷酸化将 导致丘脑阿片受体依赖性抑制的效率降低 慢性阿片类药物治疗后谷氨酸释放（受体耐受性）。磷酸化- 因此，预期MOPr缺陷型小鼠显示出比野生型小鼠更低的受体耐受性。 这些目标的结果将描述MOPr在这些丘脑-皮质-纹状体内的位置和作用。 回路，并确定受体和细胞水平的适应，导致慢性阿片类药物治疗。一 更好地了解这种电路可能会导致更好地管理这种疾病的方法或治疗方案。 治疗疼痛和限制阿片类药物的强化和奖励特性。

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.