OPIATE DEPENDENCE AND TOLERANCE

阿片类药物依赖性和耐受性

• 批准号: 3213843
• 负责人: RICHARD M EISENBERG
• 金额: $ 13.65万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-09-30 至 1994-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3213843
• 关键词: corticosterone; dosage; drug abuse chemotherapy; drug addiction; drug addiction antagonist; drug tolerance; drug withdrawal; dynorphins; endorphins; enkephalins; hormone regulation /control mechanism; hypothalamic pituitary axis; laboratory rat; morphinans; morphine; narcotic antagonists; neurotransmitter receptor; opiate alkaloid; opioid receptor; pituitary adrenal axis; radioimmunoassay; stimulant /agonist

The experiments in the proposed application are designed to extend the understanding of the influence of opiates on the hypothalamo-pituitary-adrenal (HPA) axis. The effects of specific opiate receptor ligands on plasma corticosterone secretion will be studied. Mu-agonists: DAMGO, morphiceptin, and morphine; kappa-agonists: dynorphin A(1-13), the U50-488H analogs U-69,593 or U-62,066, and tifluadom; delta-agonist: DPDPE; and the epsilon-agonist: beta-endorphin will be tested. Attempts will be made to block the effects with corresponding sub-receptor-specific antagonists and to compare responses to alternate antagonists. Antagonists to be used are the following: beta-FNA, naloxonazine, and/or naloxone; nor-BNI; naltrindole; and beta-endorphin (1-27). Through the use of such agonists and antagonists in the proposed studies, it may be possible to further define subspecies of mu and kappa-receptors. Experiments will be done to determine whether tolerance occurs to the agonist effect(s) and whether cross-tolerance occurs between alternate ligands. Using a similar chronic pretreatment, opiate specificity with respect to the initiation of both acute and chronic dependence will be determined. For the chronic studies, rats will be treated for 3 days on an escalating dose schedule with each of the opiate agonists. Corresponding subreceptor-specific antagonists will then be administered to precipitate withdrawal as indicated by changes in plasma corticosterone. These responses will be compared to those after alternate antagonists are administered. The occurrence of acute dependence/withdrawal following a single administration of an opiate will also be determined. A single dose of each specific sub-receptor agonists will be administered followed 3 hrs later by the injection of the corresponding sub-receptor-specific antagonist. Responses will be compared to those after alternate antagonists are given. Lastly, the basis for the plasma corticosterone elevation following the acute administration of high doses of naloxone or naltrexone will be examined by attempting to establish super-nominal base-lines of endogenous opiates with the enkephalinase inhibitor, acetorphan. This should determine whether homeostasis is a condition equivalent to physical dependence to endogenous opiates. These studies are made possible through the use of animals with surgically placed chronic i.v. catheters and i.c.v. injection guides. This provides for the placement into sound-attenuated one-way vision boxes to allow for serial blood sampling and i.v. and i.c.v. drug administration into conscious, unrestrained animals. The studies proposed in this application are expected to lend greater understanding of opiate control over the HPA axis, the relationships between subclasses of opiate receptors, and receptor-specificity involved with physical dependence and tolerance.

所提出的应用中的实验旨在扩展 了解阿片类药物对 下丘脑-垂体-肾上腺（HPA）轴。 特定阿片类药物的作用 将研究受体配体对血浆皮质酮分泌的影响。 Mu-激动剂：DAMGO、吗啡肽和吗啡； kappa 激动剂：强啡肽 A(1-13)，U50-488H类似物U-69,593或U-62,066，以及替氟多； δ-激动剂：DPDPE；和ε激动剂：β-内啡肽将是 已测试。 将尝试用相应的措施来阻止影响 亚受体特异性拮抗剂并比较对替代药物的反应 对手。 使用的拮抗剂如下：β-FNA， 纳洛嗪，和/或纳洛酮；去甲BNI；纳曲多；和β-内啡肽 （1-27）。 通过在提议中使用此类激动剂和拮抗剂 研究表明，有可能进一步定义 mu 和 mu 的亚种 kappa受体。 将进行实验以确定是否耐受 激动剂效应的发生以及是否发生交叉耐受 交替配体之间。 使用类似的慢性预处理，阿片类药物 急性和慢性发作的特异性 依赖性将被确定。 对于长期研究，大鼠将被 每种阿片类药物按照递增剂量方案治疗 3 天 激动剂。 相应的亚受体特异性拮抗剂将是 血浆变化表明给药可促进戒断 皮质酮。 这些响应将与之后的响应进行比较 施用替代拮抗剂。 急性发作的发生 单次服用阿片类药物后会出现依赖/戒断症状 也可以确定。 每种特定亚受体激动剂的单剂量 3小时后注射 相应的亚受体特异性拮抗剂。 回应将是 与给予替代拮抗剂后的结果相比。 最后， 急性发作后血浆皮质酮升高的依据 将检查高剂量纳洛酮或纳曲酮的施用情况 试图建立内源性阿片剂的超名义基线 与脑啡肽酶抑制剂乙酰托芬一起使用。 这应该确定 体内平衡是否相当于身体依赖 内源性阿片类药物。 这些研究是通过使用 通过手术放置慢性静脉注射的动物导管和静脉注射 注射指南。 这提供了放置到声音衰减的 单向视觉盒可进行连续血液采样和静脉注射和 静脉注射对有意识、不受约束的动物给药。 这 本申请中提出的研究预计将提供更多帮助 了解阿片类药物对 HPA 轴的控制及其关系 阿片受体亚类之间以及所涉及的受体特异性 具有身体依赖性和耐受性。