The goal of this application is to explore the mechanisms involved in mediating opioid actions, specifically those involved with morphine-6-glucuronide, heroin, and the recently cloned peptide, orphanin-FQ/nociceptin (OFQ/N). Since the cloning of the first opioid receptor, several groups including our own have used antisense probes to assess the selectivity of a specific agonists to its receptor. Our group and others have shown that there are marked differences in the receptor(s) mediating morphine and morphine-6-glucuronide through binding assays and through the use of MOR-1 and G-protein antisense studies. Furthermore, we have shown that antisense oligodeoxynucleotides targeting specific regions of the cloned mu receptor specifically downregulate morphine analgesia while failing to produce any decrease in M6G or heroin analgesia. Therefore, we believe it is important to identify the receptor subtype(s) for these agonists, while at the same time determining the possible synergistic interactions of these compounds. Recently OFQ/N has been cloned and identified as the endogenous ligand for the KOR-3/ORL-1 receptor and portrayed as a peptide that produces hyperalgesia. However, preliminary studies in our laboratory have shown that OFQ/N has analgesic actions when this peptide is assessed at longer periods of time (30-60 min). Our goal is to understand at the molecular, biochemical and pharmacological levels, the mechanisms mediating these compounds. We intend to achieve these goals through the use of antisense mapping, tolerance studies, self-administration paradigms, synergistic analgesia paradigms, strain-deficient mice, and anatomical mapping approaches.
