The overall goal of this application is to obtain a better understanding of the KOR-3 gene through its targeted disruption in mice. A novel clone, KOR-3, with high homology to the opioid receptor family has been identified by our group and others. The clone has been identified in immune cells and in an osteoblast-like cell line. Work from our group has demonstrated a close association of this clone with the kappa receptor, although the two are not the same and might result from alternative splicing of the same gene. Seven different antisense oligodeoxynucleotides derived from the KOR-3 clone selectively block kappa-3 analgesia without influencing the analgesic action of mu, delta or kappa-1 drugs and a monoclonal antibody (mAb8D8) against the natively expressed kappa3 receptor recognizes the expressed KOR-3 clone. Yet, expressed KOR-3 clone is relatively insensitive towards traditional opioids and does not demonstrate the expected binding profile of the kappa-3 receptor. The identification of a novel endogenous peptide ligand for this receptor by two independent groups opens the additional question of the physiological and pharmacological role of the endogenous ligand and the receptor encoded by the KOR-3 clone. Our goal is to understand the pharmacological and physiological significance of the KOR-3 gene product(s) by its targeted disruption in mice. Through this approach we hope to 1) establish the relationship, if any, between the KOR-3 clone and the kappa opioid receptor, 2) gain insights into the actions and importance of the recently reported endogenous ligands for the KOR-3 receptor, and 3) evaluate the functional roles of the KOR-3 gene in neuronal and non-neuronal system.