SCAFFOLDING OPIATE ANALGESIA

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