OPIOID MECHANISMS IN NITROUS OXIDE DEPENDENCE

一氧化二氮依赖的阿片类药物机制

• 批准号: 3425628
• 负责人: LINDA K VAUGHN
• 金额: $ 1.72万
• 依托单位: MARQUETTE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-09-01 至 1993-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3425628
• 关键词: alkylating agents; alkylation; analgesia; behavior test; body temperature; convulsions; dosage; drug addiction; drug adverse effect; drug withdrawal; genetic strain; injection /infusion; laboratory mouse; male; naloxone; nitrous oxide; opiate alkaloid; opioid receptor; sign /symptom

Nitrous oxide (N2O) is widely used in clinical dentistry because of its anxiolytic and analgesic properties and because it is a weak anesthetic. It is also used in medicine as an adjunct to other anesthetics. Because N2O has euphorogenic properties, there is a potential for abuse. The recreational use of N2O has increased in recent years and health professionals are especially vulnerable because N2O is easily available and the dangers of dependence are not well recognized. Because N2O produces effects similar to opioids, benzodiazepines and ethanol, mechanisms responsible for opioid, ethanol, and benzodiazepine dependence may be involved in N2O dependence. In the present proposal, we will test the hypothesis that N2O withdrawal is the result of N20-induced release of endogenous opioid peptides and subsequent dependence to the endogenous opioid peptides. Our long range goals are also to test the role of non-opioid mechanisms (i.e. mechanisms important in benzodiazepine and ethanol dependence). N2O dependence is generally measured in mice by the appearance of handling induced convulsions (HIC) after exposure to and removal from N2O. We will develop methods for evaluating dependence by identifying and measuring HIC and other N2O withdrawal signs, particularly those typically associated with opioid withdrawal. Because there are differences between mouse strains in sensitivity and responses to N2O and opioids, several mouse strains will be used. We will also test the hypothesis that the kappa and delta opioid receptor subtypes are involved in the development of dependence in response to N2O since these opioid receptor subtypes are involved in N2O-induced analgesia. We will test these hypotheses by 1) examining opioid antagonist precipitated N2O withdrawal using the nonselective opioid antagonist, naloxone, and by using antagonists selective for mu, delta, and kappa opioid subtypes, 2) examining opioid subtype selective agonist protection against N2O withdrawal, and 3) examining N2O withdrawal after alkylation of mu, delta, and kappa opioid receptors. We expect these results to increase the understanding of mechanisms which underlie dependence to N2O and, because of the similarities between N2O dependence and opioid, ethanol, and benzodiazepine dependence, to understand the mechanisms underlying dependence to a variety of drugs of abuse.

一氧化二氮（N2O）被广泛用于临床牙科 抗焦虑性和镇痛特性，因为它是一种弱麻醉性。 它也被用作其他麻醉药的辅助手段。 因为 N2O具有欣喜的特性，有滥用的潜力。 这 N2O的娱乐使用近年来有所增加和健康 专业人士特别容易受到伤害，因为N2O很容易获得 而且依赖的危险并没有得到很好的认可。 因为n2o 产生类似于阿片类药物，苯二氮卓类药物和乙醇的作用， 负责阿片类药物，乙醇和苯二氮卓依赖性的机制 可能参与N2O依赖性。 在本提案中，我们将测试 N2O退出是N20诱导释放的结果的假设 内源性阿片类肽以及随后对内源性的依赖 阿片类肽。 我们的远程目标也是测试 非阿片类药物机制（即在苯二氮卓和 乙醇依赖）。 N2O依赖性通常是通过小鼠测量的 暴露于处理后处理引起的抽搐（HIC）和 从N2O中删除。 我们将开发通过评估依赖性的方法 识别和衡量HIC和其他N2O戒断标志， 特别是那些通常与阿片类药物戒断有关的人。 因为 小鼠菌株在敏感性和反应中存在差异 对于N2O和阿片类药物，将使用几种鼠标菌株。 我们也会 检验Kappa和Delta阿片受体亚型的假设是 参与依赖性的响应N2O的发展，因为这些 阿片受体亚型参与N2O诱导的镇痛。 我们将 通过1）检查这些假设，检查阿片类药物拮抗剂沉淀N2O 使用非选择性阿片类药物拮抗剂，纳洛酮和通过 使用拮抗剂选择MU，Delta和Kappa阿片类型亚型，2） 检查阿片类型亚型选择性激动剂保护N2O 提取，3）检查Mu烷基化后N2O撤离， 三角洲和喀巴阿片受体。 我们希望这些结果会增加 对N2O依赖的机制的理解以及 由于N2O依赖性和阿片类药物之间的相似性，乙醇， 和苯二氮卓的依赖性，以了解基本机制 依赖各种虐待药物。