OPIATE DEPENDENCE AND TOLERANCE

所提出的应用程序中的实验旨在扩展 了解阿片类药物对 下丘脑-垂体-肾上腺（HPA）轴。 特定鸦片制剂的作用 将研究受体配体对血浆皮质酮分泌的影响。 μ激动剂：DAMGO、吗啡肽和吗啡; κ激动剂：强啡肽 A（1-13），U 50 - 488 H类似物U-69，593或U-62，066，和替氟多; δ-激动剂：DPDPE;和ε-激动剂：β-内啡肽将是 测试. 将尝试用相应的 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;纳曲吲哚;和β-内啡肽 （1-27）。 通过在所提出的治疗中使用这样的激动剂和拮抗剂， 研究，它可能会进一步定义亚种的亩， κ受体 将进行实验以确定是否耐受 是否发生激动剂效应以及是否发生交叉耐受 在交替的配体之间。 使用类似的慢性预处理， 急性和慢性两种疾病的启动特异性 依赖性将被确定。 对于慢性研究，大鼠将 以递增剂量方案用每种阿片剂治疗3天 激动剂 然后将相应的亚受体特异性拮抗剂 给药以促使戒断，如血浆中 皮质酮 这些反应将与之后的反应进行比较 施用替代拮抗剂。 发生急性 单次给予阿片剂后的依赖/戒断将 也要坚决。 每种特定亚受体激动剂的单次给药 将在3小时后注射 相应的亚受体特异性拮抗剂。 答复将 与给予替代拮抗剂后相比。 最后 急性脑梗死后血浆皮质酮升高的基础 将检查高剂量纳洛酮或纳洛酮的给药 试图建立内源性阿片类药物的超标称基线， 脑啡肽酶抑制剂乙酰吗啡芬 这将决定 体内平衡是否等同于身体依赖 内源性鸦片 这些研究是通过使用 用手术放置的慢性i. v.导管和i. c. v. 注射指南。 这提供了放置到声音衰减 单向观察盒，用于连续采血和静脉注射， 将药物i. c. v.给药至清醒的、不受限制的动物。 的 本申请中提出的研究预计将提供更大的 了解阿片类药物对HPA轴的控制， 阿片受体的亚类之间，和受体特异性涉及 身体依赖和耐受性。

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.