It is now recognized that co-localized opioid, adrenergic and other GPCRs may be associated as dimers and oligomers in addition to the traditionally envisaged monomeric species. These developments have resulted in considerable re-evaluation of our models of GPCR structure and function. Although many reports of GPCR oligomerization now exist, the vast majority of studies have been conducted in transfected cells in vitro. In fact, there are very few reports investigating the existence of GPCR heteromers in vivo. The significance and role of oligomerization in GPCR function in CNS tissue therefore remains largely unexplored. Agonists acting at spinal delta-opioid and alpha-2A-adrenergic receptors inhibit pain transmission and interact synergistically when co-administered in the spinal cord and are highly co-localized in primary afferent neurons (an obvious prerequisite for oligomerization). We propose to utilize these receptor subtypes as a physiologically relevant model to explore the functional implications and importance of GPCR oligomerization in the CNS. We propose a series of studies designed to directly identify heteromeric species in CNS tissue. In addition, we will explore the nature of these interaction(s) at the molecular and cellular levels to identify a potential role for GPCR heteromerization in analgesic synergy. Improving our understanding of the existence of and functional implications of oligomerization in opioid receptor biology could lead to insights into the cellular and molecular mechanisms of analgesic synergy, tolerance and dependency. These studies could therefore have a significant impact in future drug discovery and treatment approaches to narcotic addiction and the treatment of severe acute and chronic pain.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21DA017075-01
Application #
6702686
Study Section
Special Emphasis Panel (ZDA1-TXL-Q (35))
Program Officer
Thomas, David A
Project Start
2003-09-01
Project End
2005-05-31
Budget Start
2003-09-01
Budget End
2004-05-31
Support Year
1
Fiscal Year
2003
Total Cost
$148,500
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Neurosciences
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Chabot-Doré, Anne-Julie; Millecamps, Magali; Naso, Lina et al. (2015) Dual allosteric modulation of opioid antinociceptive potency by ?2A-adrenoceptors. Neuropharmacology 99:285-300
Stone, Laura S; German, Jonathan P; Kitto, Kelly F et al. (2014) Morphine and clonidine combination therapy improves therapeutic window in mice: synergy in antinociceptive but not in sedative or cardiovascular effects. PLoS One 9:e109903
Fairbanks, Carolyn A; Stone, Laura S; Wilcox, George L (2009) Pharmacological profiles of alpha 2 adrenergic receptor agonists identified using genetically altered mice and isobolographic analysis. Pharmacol Ther 123:224-38
Riedl, Maureen S; Schnell, Stephen A; Overland, Aaron C et al. (2009) Coexpression of alpha 2A-adrenergic and delta-opioid receptors in substance P-containing terminals in rat dorsal horn. J Comp Neurol 513:385-98
Stone, Laura S; Kitto, Kelley F; Eisenach, James C et al. (2007) ST91 [2-(2,6-diethylphenylamino)-2-imidazoline hydrochloride]-mediated spinal antinociception and synergy with opioids persists in the absence of functional alpha-2A- or alpha-2C-adrenergic receptors. J Pharmacol Exp Ther 323:899-906