Mechanisms of Ethanol's Reversal of Opioid Tolerance

乙醇逆转阿片类药物耐受性的机制

基本信息

批准号：
8786757
负责人：
HAMID I AKBARALI
金额：
$ 45.21万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8786757
关键词：
Acute Affect Alcohol abuse Alcohol consumption Alcohols Animals Autopsy Benzodiazepines Blood Brain Buprenorphine Central Nervous System Depressants Cessation of life Chronic Constipation Cyclic AMP-Dependent Protein Kinases Data Development Diazepam Dose Enkephalin, Ala(2)-MePhe(4)-Gly(5)-Ethanol Event Forensic Medicine GABA Receptor Gastrointestinal tract structure Genetically Modified Animals Goals Grant Heroin Individual Investigation Laboratories Link Literature Maintenance Therapy Mediating Methadone Molecular Morphine Mus Neuraxis Opiate Addiction Opiates Opioid Oxycodone Peripheral Pharmaceutical Preparations Pharmacology Physiology Protein Kinase C Inhibitor Publishing Receptor Signaling Recording of previous events Reporting Research Rewards Role Scientist Self-Administered Spinal System Techniques Testing Ventilatory Depression Work alcohol effect base drug of abuse drug testing experience inhibitor/antagonist neurophysiology prescription opioid public health relevance receptor research study respiratory reverse tolerance

项目摘要

DESCRIPTION (provided by applicant): There is considerable evidence in the literature that deaths due to the simultaneous abuse of ethanol with opioids such as heroin or prescription opioids leads to lower blood levels of the opioid upon autopsy than is observed following death due to the opioid alone. We have carried out an extensive study which has shown that either ethanol or diazepam at doses that do not alter the acute effects of morphine reversed the antinociceptive tolerance produced by chronic morphine. The mechanism of the reversal produced by the two drugs differed in that inhibitors of either GABAA or GABAB receptors alone did not reverse the effect of alcohol but blocking both type GABA receptors completely reversed the effect of ethanol on morphine tolerance. Conversely the inhibition of morphine tolerance produced by diazepam was completely reversed by a GABAA inhibitor alone but not by the GABAB inhibitor. The overall objective of the work described in this proposal is to elucidate the cellular mechanisms by which opioid tolerance is reversed by the concomitant administration of ethanol and other agents affecting the central nervous system. Using genetically altered mice and a number of molecular techniques we will elucidate further the role of GABA receptors and the signaling mechanisms involved in these effects. In the second specific aim we propose to elucidate whether ethanol and diazepam reverses the tolerance to opioids such as buprenorphine and methadone which are used in maintenance therapy and oxycodone and other prescription opioids with a history of abuse. We and others have reported differences in the mechanism of tolerance development for various opioids. For instance, protein kinase A and protein kinase C inhibitors but not GIRK inhibitors reversed tolerance to morphine and other moderately efficacious opioids but not to the high efficacy DAMGO. GIRK inhibitors revered the tolerance to DAMGO but not the other opioids. These differences in the mechanism of tolerance development to various opioids cause us to investigate whether ethanol and/or diazepam will reverse the tolerance to opioids of various efficacies. Obviously, we will elucidate the differing mechanisms if the opioids are affected differently by ethanol or diazepam. In the third specific aim we will investigate whether ethanol and diazepam also reverse tolerance to a peripheral effect of opioids. We and others have found certain differences between the mechanisms of opioid tolerance in the brain and the gastrointestinal tract and now we propose to determine whether ethanol and/or diazepam reverses opioid tolerance in the gastrointestinal tract. The information gained from these experiments will provide important information as we and others continue to elucidate the mechanism of opioid tolerance.

描述（由申请人提供）：文献中有大量证据表明，同时滥用乙醇和阿片类药物（例如海洛因或处方阿片类药物）导致的死亡导致尸检时阿片类药物的血液水平低于阿片类药物死亡后观察到的血液水平独自的。我们进行了一项广泛的研究，结果表明，在不改变吗啡急性作用的剂量下，乙醇或地西泮可以逆转慢性吗啡产生的镇痛耐受。两种药物产生逆转作用的机制不同，单独使用 GABAA 或 GABAB 受体抑制剂并不能逆转酒精的作用，但阻断这两种类型的 GABA 受体则可以完全逆转乙醇对吗啡耐受的影响。相反，地西泮产生的吗啡耐受性抑制作用可被单独的 GABAA 抑制剂完全逆转，但不能被 GABAB 抑制剂逆转。本提案中描述的工作的总体目标是阐明通过同时施用乙醇和其他影响中枢神经系统的药物来逆转阿片类药物耐受的细胞机制。使用基因改造小鼠和许多分子技术，我们将进一步阐明 GABA 受体的作用以及参与这些作用的信号机制。在第二个具体目标中，我们建议阐明乙醇和地西泮是否会逆转对阿片类药物的耐受性，例如用于维持治疗的丁丙诺啡和美沙酮以及羟考酮和其他有滥用史的处方阿片类药物。我们和其他人报告了各种阿片类药物耐受性发展机制的差异。例如，蛋白激酶 A 和蛋白激酶 C 抑制剂（而非 GIRK 抑制剂）可以逆转对吗啡和其他中等有效阿片类药物的耐受性，但不能逆转对高效 DAMGO 的耐受性。 GIRK 抑制剂尊重 DAMGO 的耐受性，但不尊重其他阿片类药物。对各种阿片类药物的耐受性发展机制的这些差异促使我们研究乙醇和/或地西泮是否会逆转对各种功效的阿片类药物的耐受性。显然，如果阿片类药物受到乙醇或地西泮的不同影响，我们将阐明不同的机制。在第三个具体目标中，我们将研究乙醇和地西泮是否也能逆转对阿片类药物外周作用的耐受性。我们和其他人发现大脑和胃肠道中阿片类药物耐受的机制之间存在某些差异，现在我们建议确定乙醇和/或地西泮是否可以逆转胃肠道中的阿片类药物耐受。从这些实验中获得的信息将为我们和其他人继续阐明阿片类药物耐受机制提供重要信息。