OPIATE DEPENDENCE AND TOLERANCE

应用程序中的实验旨在扩展应用程序

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.