Opioids such as morphine are highly prescribed for moderate to severe pain, however, their euphoric properties contribute to their widespread abuse. The ?-opioid receptor is primarily responsible for both the analgesic and euphoric effects, while agonists at the d -opioid receptor retain some analgesic properties, but have a lower abuse liability and have been suggested to attenuate some of the negative effects of ? agonists. For instance, eliminating the action of the d -receptor blocks the development of morphine tolerance and dependence in rodents. This interaction could be explained by heterodimerization of ? and d receptors, or by compartmentalization into membrane microdomains, such as lipid rafts, to form functional signaling complexes. In support of this, ? and d receptors colocalize in certain brain neurons and can heterodimerize in biochemical assays, while n and K receptors localize to lipid rafts with functional signaling consequences. The hypothesis of this proposal is that lipid rafts are required for ? and d -opioid receptor pharmacology including cross-talk.
Two specific aims have been designed to test this hypothesis. The goal of specific aim #1 is to investigate the role of lipid rafts on ? and d receptor signaling by addressing the following questions: a) Are ? and d receptors and their associated signaling proteins localized to lipid rafts? and b) Are lipid rafts required for efficient signaling of ? and d receptors and for cross-talk between these receptors? All experiments in aim 1 will be performed in HEK293 cells expressing epitope-tagged ? and/or d receptors. The goal of specific aim #2 is to determine the impact of cholesterol-lowering on ?/ d receptor interactions in vivo, by measuring ? and d agoinst-mediated antinociception, tolerance and dependence in mice treated with the clinically-used cholesterol-lowering agent simvastatin. The effect of cholesterol-lowering on opioid signaling will provide insight into the mechanism behind the cross-talk between ? and d receptors. This understanding could lead to the development of highly efficacious analgesics with a decreased abuse liability. Generally, the effect of cholesterol-lowering on opioid and GPCR signaling is important to study because of the increasing use of cholesterol-lowering agents and the continuously lowering clinical cholesterol goals.
| Levitt, Erica S; Purington, Lauren C; Traynor, John R (2011) Gi/o-coupled receptors compete for signaling to adenylyl cyclase in SH-SY5Y cells and reduce opioid-mediated cAMP overshoot. Mol Pharmacol 79:461-71 |
| Levitt, Erica S; Clark, Mary J; Jenkins, Paul M et al. (2009) Differential effect of membrane cholesterol removal on mu- and delta-opioid receptors: a parallel comparison of acute and chronic signaling to adenylyl cyclase. J Biol Chem 284:22108-22 |
