Microglia and Opioid Withdrawal

与海洛因等非法药物的使用和滥用有关的阿片类药物过量流行 处方麻醉性止痛药。长期使用阿片类药物，即使在医疗监督下也是如此 这与容忍度的形成和退出风险的不断上升有关。阿片类药物的戒断 综合症是一个严重的医学问题，可能成为吸毒者继续使用阿片类药物的主要原因。 目前预防戒断综合症的唯一治疗方法是要么继续服用阿片类药物 (包括美沙酮等替代药物)或对许多严重问题进行对症处理 如腹泻、呕吐、脱水、抽筋、肌肉疼痛、失眠、易怒和焦虑。上瘾 个人往往更愿意继续吸毒，而不是面临戒断。而莫阿片类药物的突然减少 受体激活是戒断的近端原因，令人惊讶的是，人们对下游是如何变化的知之甚少。 生理过程导致了这种综合征。“吸毒成瘾”有许多严重的特征 炎症状态。因此，毫不奇怪，越来越多的证据表明，阿片类药物耐受性和 尤其是急性戒断会产生一种神经炎性状态，这是导致症状的主要因素。 经验丰富。 我们提出的假设是，小胶质细胞，大脑中的常驻免疫细胞，在 阿片类药物的戒断以及这些细胞介导的炎性级联反应导致了大部分的戒断 综合症。我们将使用两种策略来测试这一想法。首先，我们将测量小胶质细胞中的RNA 正在被积极地翻译成蛋白质(作为被激活的生物途径的指示器 这些细胞在停药期间)。我们将研究给予剂量不断增加的吗啡的小鼠，然后 然后使用RiboTag，一种从特定细胞中提取RNA的新技术 类型，以询问小胶质细胞在阿片类药物戒断后激活过程中发生的顺序变化。 其次，我们将评估是否可以通过抑制小胶质细胞的激活来预防戒断综合征 在戒断过程中使用经过改造的“DREADD”受体抑制小胶质细胞。这些实验将利用 在我们实验室建立的最先进的转基因策略，将使我们能够前所未有地精确地 急性阿片类药物戒断过程中小胶质细胞的研究与调控。这项提议的最终目标是 在小胶质细胞中发现新的分子靶点，可以预防与戒断相关的炎症， 导致开发新的治疗方法来缓解阿片类药物的戒断。这将使撤资本身 更安全，并可能有助于成瘾个人停止使用阿片类药物的动机。

There is an epidemic of opioid overdoses associated with the use of illicit drugs such as heroin and the misuse of prescribed narcotic pain medications. Chronic use of opioids, even when under medical supervision, is associated with the development of tolerance and escalating risk of withdrawal. The opioid withdrawal syndrome is a serious medical problem that can become a major reason why addicts keep using opioid drugs. Currently the only treatments to prevent the withdrawal syndrome are either continuing to take opioids (including substitution drugs such as methadone) or symptomatic management of the many severe problems such as diarrhea, vomiting, dehydration, cramping, muscle pain, insomnia, irritability, and anxiety. Addicted individuals often prefer to continue drugs rather than face withdrawal. While the sudden reduction in mu opioid receptor activation is the proximal cause of withdrawal, surprisingly little is known about how downstream physiological processes contribute to the syndrome. Being “dope-sick” has many attributes of a severe inflammatory state. Thus, it is not surprising that evidence is accumulating that both opioid tolerance and especially acute withdrawal produce a neuroinflammatory state that is a major contributor to the symptoms experienced. We propose the hypothesis that microglia, the resident immune cells in the brain, become activated during opioid withdrawal and that the inflammatory cascades mediated by these cells lead to much of the withdrawal syndrome. We will test this idea using two strategies. First, we will measure the RNAs in microglia cells that are actively being translated to make protein (as indicators of the biological pathways that are activated in these cells during withdrawal). We will investigate mice given escalating doses of morphine followed by precipitated withdrawal and then use RiboTag, a new technology for retrieving the RNA from specific cell types, to interrogate the sequential changes occurring during microglial activation from opioid withdrawal. Second, we will assess whether the withdrawal syndrome can be prevented by inhibiting microglial activation using engineered “DREADD” receptors to inhibit microglia during withdrawal. These experiments will utilize state of the art transgenic strategies that are established in our lab and will allow us unprecedented precision in investigating and modulating microglia during acute opioid withdrawal. The ultimate goal of this proposal is to identify novel molecular targets in microglia that can prevent the inflammation associated with withdrawal, leading to the development of new treatments to mitigate opioid withdrawal. This will make withdrawal itself safer and potentially contribute to the motivation of addicted individuals to discontinue opioid use.