? Opioid and adrenergic agonists produce analgesia synergistically at G protein-coupled receptors (GPCR). Opioid tolerance and neuropathic pain both involve neuronal plasticity that may decrease this synergistic relationship. The proposed research will 1) determine how synergistic interactions occur between opioid receptor (OR) and alpha-2 adrenergic receptor (AR) agonists, 2) compare the mechanisms underlying GPCR-mediated analgesic synergism under normal conditions and in states of neuronal plasticity, and 3) examine the functional relationships between OR and AR transmitters. We will test the following hypotheses: Hypothesis 1A - Synergistically acting receptor pairs sharing localization couple through different intracellular pathways; Hypothesis 1B - Synergistically interacting receptor pairs coupling through the same intracellular pathways reside in different locations; Hypothesis 2 - Persistent alterations in receptor distribution or coupling driven by neural plasticity impact potency or efficacy of analgesic agonists by changing interactions between receptor subtypes. Behavioral studies will examine the mechanism of spinal analgesic synergy under normal, opioid tolerant, and neuropathic conditions. Immunohistochemical localization of OR/AR and quantification of transmitter release from spinal cord slices will define the anatomical substrates for the functional interactions observed. Electrophysiology of dorsal horn neurons will examine the cellular mechanisms of drug action and interaction at the single cell level. The information gained from these studies may identify new therapeutic analgesic combinations and combination receptor targets leading toward reduction of dependence liabilities of analgesic treatments. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA015438-03
Application #
7061325
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Thomas, David A
Project Start
2004-07-15
Project End
2009-04-30
Budget Start
2006-05-01
Budget End
2007-04-30
Support Year
3
Fiscal Year
2006
Total Cost
$326,274
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
Peterson, Cristina D; Kitto, Kelley F; Akgün, Eyup et al. (2017) Bivalent ligand that activates mu opioid receptor and antagonizes mGluR5 receptor reduces neuropathic pain in mice. Pain 158:2431-2441
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
Chabot-Doré, A-J; Schuster, D J; Stone, L S et al. (2015) Analgesic synergy between opioid and ?2 -adrenoceptors. Br J Pharmacol 172:388-402
Schuster, D J; Metcalf, M D; Kitto, K F et al. (2015) Ligand requirements for involvement of PKC? in synergistic analgesic interactions between spinal ? and ? opioid receptors. Br J Pharmacol 172:642-53
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
Schuster, Daniel J; Kitto, Kelley F; Overland, Aaron C et al. (2013) Protein kinase C? is required for spinal analgesic synergy between delta opioid and alpha-2A adrenergic receptor agonist pairs. J Neurosci 33:13538-46
Metcalf, Matthew D; Yekkirala, Ajay S; Powers, Michael D et al. (2012) The ? opioid receptor agonist SNC80 selectively activates heteromeric ?-? opioid receptors. ACS Chem Neurosci 3:505-9
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
Fairbanks, Carolyn A; Kitto, Kelley F; Nguyen, H Oanh et al. (2009) Clonidine and dexmedetomidine produce antinociceptive synergy in mouse spinal cord. Anesthesiology 110:638-47

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