Mechanisms of Ethanol's Reversal of Opioid Tolerance

乙醇逆转阿片类药物耐受性的机制

• 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
• 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

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，与仅因阿片类药物死亡后观察到的水平相比，因同时滥用乙醇和阿片类药物（如海洛因或处方阿片类药物）而导致的死亡导致尸检时阿片类药物的血液水平较低。我们进行了一项广泛的研究，结果表明，无论是乙醇还是地西泮，在不改变吗啡急性效应的剂量下，都能逆转慢性吗啡产生的抗伤害性耐受。这两种药物产生的逆转机制不同，因为单独的GABAA或GABAB受体抑制剂不能逆转酒精的作用，但阻断两种类型的GABA受体完全逆转了酒精对吗啡耐受的作用。相反，地西泮产生的吗啡耐受的抑制被单独的GABAA抑制剂完全逆转，但不能被GABAB抑制剂逆转。本提案中所述工作的总体目标是阐明伴随给予乙醇和其他影响中枢神经系统的药物逆转阿片类药物耐受性的细胞机制。使用基因改变的小鼠和一些分子技术，我们将进一步阐明GABA受体的作用和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逆转对阿片类药物的耐受性，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对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抑制剂而不是GIRK抑制剂逆转了对吗啡和其他中度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抑制剂可抑制对DAMGO的耐受性，但对其他阿片类药物则无影响。对各种阿片类药物的耐受性发展机制的这些差异使我们研究乙醇和/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逆转对阿片类药物外周效应的耐受性。我们和其他人已经发现阿片类药物耐受性在大脑和胃肠道的机制之间存在一定的差异，现在我们建议确定乙醇和/或地西泮是否逆转胃肠道中的阿片类药物耐受性。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的机制提供重要信息。