OPIATE DEPENDENCE AND TOLERANCE

建议的应用程序中的实验旨在扩展 对阿片类药物影响的认识 下丘脑-垂体-肾上腺(HPA)轴。特异性阿片类药物的作用 受体配体对血浆皮质酮分泌的影响将被研究。 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和替氟多姆； 增量激动剂：DPDPE；和肾上腺素激动剂：β-内啡肽 测试过。将尝试通过相应的方法来阻止这些效果 亚受体特异性拮抗剂，并比较替代药物的反应 对抗者。使用的拮抗剂如下：β-FNA， 纳洛酮和/或纳洛酮；Nor-BNI；纳曲哚；和β-内啡肽 (1-27)。通过使用这种激动剂和拮抗剂在拟议的 研究表明，有可能进一步确定Mu和Mu的亚种 Kappa受体。将进行实验以确定是否存在耐受性 发生激动剂效应(S)和是否发生交叉耐受 在交替的配基之间。使用类似的慢性预处理，阿片类药物 关于急性和慢性两种疾病启动的特异性 依赖性将被确定。对于慢性研究，老鼠将被 每种阿片类药物按递增剂量计划治疗3天 激动剂。相应的亚受体特异性拮抗剂将被 用来催促戒断，如血浆变化所示 皮质酮。这些回答将与之后的回答进行比较 使用交替使用的拮抗剂。急性冠脉综合征的发生 单次服用阿片类药物遗嘱后的依赖/戒断 也要有决心。每种特定亚受体激动剂的单剂量 将在3小时后注射 相应的亚受体特异性拮抗剂。回应将是 与给予交替拮抗剂后的结果相比。最后， 急性心肌梗死后血浆皮质酮升高的基础 将检查大剂量纳洛酮或纳曲酮的使用情况 通过试图建立内源性阿片类药物的超标称基线 使用脑啡肽酶抑制剂，乙酰吗啡。这应该决定 动态平衡是否等同于身体依赖 内源性鸦片类药物。这些研究是通过使用 接受手术的慢性静脉注射的动物。导管和静脉注射。 注射导轨。这提供了放置到声音衰减的位置 允许连续采血和静脉注射的单向视觉盒。和 I.C.V.给有意识的、无拘无束的动物注射药物。这个 本申请中提出的研究有望提供更多 了解阿片类药物对HPA轴的控制及其相互关系 阿片受体亚类之间的关系以及涉及的受体特异性 身体上的依赖性和容忍度。

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.