How does ethanol alter opioid tolerance?

在酒精饮料中消耗的乙醇经常被发现与阿片类药物过量死亡的海洛因或美沙酮一起存在沿着。因此，确定乙醇如何与阿片类药物相互作用以增加其非法使用的危险是极其重要的。我们自己的工作中有证据表明，急性暴露于低剂量乙醇会降低对吗啡的呼吸抑制和镇痛作用的耐受性，而慢性乙醇消耗似乎会降低阿片类药物的镇痛效果。这表明乙醇影响阿片类药物作用的方式可能存在差异，这取决于乙醇消耗的性质（间歇性v慢性摄入）。因此，本提案中所述研究的目的是确定分子水平，细胞和行为水平急性和慢性乙醇给药如何改变对阿片类药物呼吸抑制作用的耐受水平-服用这些药物与过量死亡有关的最重要的生理后果。我们将试图在分子和细胞水平上阐明发展对阿片类药物的呼吸抑制作用的耐受性，然后确定乙醇如何影响这些耐受性。不同的阿片类药物被认为是通过不同的细胞机制诱导耐受性，这增加了乙醇可能不同地影响对不同阿片类药物的耐受性的可能性。出于这个原因，我们将研究耐受性如何发展到一系列阿片类药物，用于治疗阿片类药物成瘾，并确定急性和慢性乙醇给药对每种药物的耐受性的影响。我们将结合联合收割机呼吸与电生理记录从神经元在大脑中控制呼吸和阿片类药物信号和耐受性的重要介质的体外分子研究的整个动物研究。我们的实验结果将为阿片类成瘾者合并使用酒精和阿片类药物的危险提供重要的新信息，并提供科学证据，以提供适当的重要公共卫生信息。

Ethanol, consumed in alcoholic beverages, is frequently found to be present along with heroin or methadone in opioid overdose fatalities. It is therefore extremely important to determine exactly how ethanol may be interacting with opioid drugs to enhance the dangers of their illicit use. There is evidence from our own work to suggest that acute exposure to low doses of ethanol can reduce tolerance to the respiratory depressant and analgesic actions of morphine whereas chronic ethanol consumption appears to reduce the analgesic effectiveness of opioid drugs. This suggests that there may be differences in the way ethanol affects the actions of opioids depending upon the nature of ethanol consumption (intermittent v chronic intake). The aim of the research described in this proposal is therefore to determine at the molecular, cellular and behavioural levels how acute and chronic ethanol administration can alter the level of tolerance to the respiratory depressant effects of opioids - the most important physiological consequence of taking these drug in relation to death in overdose.We will seek to elucidate at the molecular and cellular levels the signaling mechanisms underlying the development of tolerance to the respiratory depressant actions of opioid drugs and then determine how these can be affected by ethanol. Different opioid drugs are thought to induce tolerance by distinct cellular mechanisms raising the possibility that ethanol could differentially affect tolerance to different opioid drugs. For this reason we will study how tolerance develops to a range of opioids that are used illicitly and in the therapy of opioid addiction and determine the effects of acute and chronic administration of ethanol on the tolerance to each drug. We will combine whole animal studies of respiration with electrophysiological recording from neurones in the brain that control respiration and in vitro molecular studies of important mediators of opioid signaling and tolerance. The results from our experiments will provide important new information on the dangers of the combined use of alcohol and opioids by opioid addicts and provide scientific evidence on which appropriate, important public health messages can be based.