The primary objective of this project continues to be the in vivo study of the receptors involved in the actions of opioids and endogenous opioids. The focus is on the roles played by the endogenous opioid systems in normal homeostasis and in perturbed homeostasis, including opioid tolerance and dependence. Our previous research has allowed us to begin to delineate the roles of the endogenous opioid system in thermoregulation, analgesia, and cerebral excitability. Using selective agonists and antagonists, we will continue our efforts by examining how the opioid receptor subsystems interact with each other to affect these roles. In addition, because it is our belief that the interplay of neuropeptides is crucial for most physiological systems, we will investigate the interaction between the opioid systems and selected other neuropeptide systems. Dose-response curves will be generated in all cases and routes of administration will be chosen based on the pharmacokinetics of the drugs being tested and the questions being asked. Chronic administration of drugs will be used to study how the usual roles of the receptors and the interactions with other neuropeptide systems are modified by repeated administration of drugs. The opioid receptor types that will receive primary attention are mu and kappa, although other types of opioid receptors, especially delta, will be studied when appropriate. Neuropeptides to be examined include cholecystokinin, substance P, somatostatin, neurotensin, and TRH. Measurements will be made of body temperature, antinociception, and seizure thresholds. Techniques to be used include calorimetry, in vivo microdialysis, RIA, and HPLC. The ultimate goal of these studies is to understand the functions of the endogenous opioid systems, the mechanisms involved in those actions, and how chronic administration of opioids affects those roles. Such knowledge will not only provide greater insight into the consequences of chronic use of opioids, but may well lead to improved therapies for pathological states involving pain, disruption of thermoregulation, or altered cerebral excitability.