Recent evidence has provided support for the view that multiple opioid delta receptors exists in the brain, in the spinal cord and in the periphery. While the identification of subtypes of opioid delta receptors provides an opportunity to explore further the physiological and pharmacological importance of the delta receptor system, progress towards this end has been hampered by the lack of highly selective, and systemically active, delta receptor agonist, partial agonist and antagonists. This portion of the Program Project application will focus on two main objectives: first, a detailed pharmacological analysis of novel delta subtype selective ligands synthesized by the chemistry section and identified in the Biological Analysis Core will be carried out. This analysis will focus on the identification of receptor subtype selectivity using methods in vitro and in vivo for analogues deemed interesting from the result of the Core. A second goal of this section of the Program Project is to explore the pharmacology of the delta receptor system in naive and delta-agonist or antagonist exposed animal, tissues and cells. A particular goal of this effort is to established whether occupation of opioid delta receptors by agonist, partial agonist, or antagonist will prevent the development of expression of the opiate abstinence syndrome. Further, studies will be carried out to determine whether a delta receptor abstinence syndrome can be demonstrated in rodents and if so, its characteristics and relationship to one or more of the delta receptor subtypes. The objective of these studies is to continue to add to our fundamental understanding of the opioid delta receptor, and its subtypes. The results of both of these efforts will be closely tied to the synthetic effort, not only in evaluating molecules already synthesized, but also in order to further aid the synthesis of new highly delta-subtype selective (i.e., 1,000-fold) agonist and antagonists. The information gained in these objectives will help in testing the hypothesis that opioid delta receptor agonist, partial agonist or antagonists will eventually have therapeutic utility in management of pain and addiction.
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