BEHAVIORAL STUDIES OF OPIOID TOLERANCE AND DEPENDENCE

阿片类药物耐受性和依赖性的行为研究

• 批准号: 2654340
• 负责人: ALICE M YOUNG
• 金额: $ 29.73万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-02-01 至 2002-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2654340
• 关键词: NMDA receptors; analgesics; behavior test; behavioral /social science research tag; buprenorphine; cholecystokinin; drug abuse chemotherapy; drug tolerance; enzyme inhibitors; fentanyl; laboratory rat; morphine; naltrexone; narcotic antagonists; nitric oxide synthase; operant conditionings; opiate alkaloid; pigeons; psychopharmacology; stimulant /agonist

DESCRIPTION: (Applicant's Abstract) Current treatments for human opioid abuse incorporate a variety of chronic pharmacotherapies, including methadone maintenance and newer or experimental treatments with low efficacy opioid agonists (e.g., buprenorphine) or opioid antagonists (e.g., naltrexone). Preclinical studies of the behavioral sequelae of such maintenance therapies may be useful in predicting their psychomotor and subjective effects in humans. The proposed projects will use drug discrimination assays as a model system to assess how pharmacological and behavioral factors modulate development of tolerance during repeated treatment with selected opioid agonists, alone and in combination with non-opioid agents proposed to modulate opioid tolerance and/or dependence. We will pay particular attention to patterns of tolerance and cross-tolerance among opioids that appear to differ in intrinsic efficacy as agonists. Related experiments will evaluate several behavioral effects of opioids in opioid-dependent subjects, and in subjects treated with irreversible opioid receptor antagonists. The first proposed project will characterize patterns of tolerance and cross-tolerance to discriminative stimulus and antinociceptive effects of mu opioids as a function of agonist efficacy. Planned studies will focus on chronic administration of low efficacy mu agonists. The second project will study antagonism of antinociceptive and stimulus effects of agonists by irreversible antagonists, in order to provide an independent test of the hypothesis that differences in tolerance are related to differences in relative intrinsic efficacy. The third and fourth projects will characterize acute and chronic interventions that may modulate development of opioid tolerance or dependence. Specific compounds to be studied include putative neutral opioid antagonists, kinase inhibitors, NMDA-antagonists CCK-antagonists and NO synthase inhibitors. Experiments will determine effects of acute and chronic treatment with selected agents on development and expression of tolerance and dependence, using behavioral assays of antinociception, acute dependence, and discriminative stimulus effects of mu opioids.

描述：（申请人的摘要） 当前对人阿片类药物滥用的治疗方法包括各种慢性 药物治疗，包括美沙酮维护以及更新或实验 低疗效阿片类药物激动剂（例如丁丙诺啡）或阿片类药物的治疗 拮抗剂（例如纳曲酮）。 行为的临床前研究 这种维持疗法的后遗症可能有用 人类的心理运动和主观影响。 拟议的项目将 使用药物歧视测定法作为模型系统来评估 药理和行为因素调节公差的发展 在与选定阿片类药物激动剂的重复治疗过程中，单独和 与提议调节阿片类药物耐受性的非阿片类药物的结合 和/或依赖。 我们将特别注意 阿片类药物的耐受性和交叉耐受性似乎有所不同 作为激动剂的内在功效。 相关实验将评估几个 阿片类药物在阿片类药物依赖性受试者和受试者中的行为影响 用不可逆的阿片类受体拮抗剂治疗。 第一个提议 项目将表征耐受性和交叉耐受模式 MU阿片类药物作为A 激动剂功效的功能。 计划的研究将重点放在慢性上 低功效MU激动剂。 第二个项目将研究 激动剂的抗伤害感受和刺激作用的拮抗作用 不可逆转的拮抗剂，以提供对 假设公差的差异与差异有关 相对内在功效。 第三和第四个项目将 表征可能调节发展的急性和慢性干预措施 阿片类药物耐受性或依赖性。 要研究的特定化合物包括 假定的中性阿片类药物拮抗剂，激酶抑制剂，NMDA抗抗激素 CCK-抗逆邦剂和无合酶抑制剂。 实验将确定 急性和慢性治疗对选定剂的发育影响 以及使用行为测定法 抗伤害感受，急性依赖性和MU的歧视性刺激作用 阿片类药物。