Scaffolding Opiate Analgesia

摘要

ABSTRACT The long-term goal of this research project is to understand the role of scaffolding proteins in the regulation of opioid receptors. Opioids are commonly administered as systemic analgesics to treat acute, chronic, and intractable pain syndromes. However, activation of mu opioid receptors (MOPr) throughout the central nervous system produces negative side effects that often contraindicate continued use. Targeting peripheral MOPr reduces pain and circumvents systemic side effects (Stein et al., 2003), yet peripheral opioid receptors behave differently than those expressed in the central nervous system, and their regulation is poorly understood. This represents a large gap in knowledge and an important unmet need, since the careful identification of contributors to opioid receptor responsiveness in the periphery would provide new, peripheral therapeutic targets for analgesic drug development. The overall objective of this application is to determine whether the scaffolding protein A-Kinase Anchoring Protein 79/150 (AKAP) regulates MOPr responsiveness. The central hypothesis for this study is that AKAP supports MOPr signaling. This hypothesis will be addressed through two specific aims that (1) determine the contribution of AKAP to MOPr signaling in sensory neurons and (2) evaluate AKAP association with MOPr. AKAP regulation of signaling pathways downstream of MOPr will be investigated through a combination of pharmacological, biochemical, and molecular techniques. Furthermore, primary sensory neuron cultures will be utilized to increase translational relevance with future behavioral studies. The contribution of this research is significant because it is the first step towards identifying specific regulatory components of the peripheral opioid receptor signaling system. Together with preliminary data, research results will demonstrate that AKAP association with MOPr positively regulates signaling downstream of the receptor, thereby increasing opioid analgesia.