Peripherally acting opioids are desirable for producing analgesia while eliminating debilitating central side effects, such as tolerance, dependence and addiction. However, peripheral opioid efficacy is significantly reduced in the absence of tissue inflammation. The long-term goal of this research project is to understand how inflammation enhances peripheral opioid efficacy. For example, in the absence of inflammation the delta opioid receptor (DOR) is less responsive to agonist activation. However, inflammatory mediators have been shown to enhance receptor responsiveness and increase peripheral opioid efficacy. Therefore, the constitutively desensitized receptor becomes primed for activation following inflammation. A gap in knowledge exists concerning the mechanism regulating constitutive DOR incompetence. This represents an important opportunity to identify new pharmaceutical targets to enhance opioid efficacy. The overall objective of this project is to identify that G protein-coupled receptor kinase 2 (GRK-2) chronically associates with DOR to govern receptor competence. The central hypothesis for this application is that GRK-2 constitutively desensitizes DOR and that its dissociation from the receptor enhances DOR responsiveness. This hypothesis will be addressed through three specific aims that (1) identify whether the association of GRK-2 with DOR governs receptor competence, (2) determine whether AKAP mediates constitutive association of GRK-2 with DOR, and (3) investigate whether PLC activity drives DOR priming. The role of GRK-2 on DOR competence will be investigated using a combination of biochemical, molecular, genetic, imaging, and behavioral techniques. The contribution of this research is significant because it will identify new targets t increase opioid agonist efficacy. Research results will demonstrate that reducing chronic GRK-2 association with DOR can significantly enhance DOR competence and improve analgesic efficacy.