Opioid receptors have been targeted for the treatment of pain and related conditions for thousands of years. Three opioid receptors have been characterized, with a fourth opioid receptor called nociceptin (NOPR) or opioid-receptor like-1 being the newest member of the family. Recent evidence has shown that opioid receptors are potentially novel targets for addiction, anxiety, and depression. Furthermore, reports suggest that the NOPR - nociceptin system is involved in cocaine reward behavior. However, where in the brain NOPR receptors modulate these behaviors, how NOPR is regulated, and how it signals has not been defined. In order to better understand the role of this system in behavior we propose 2 aims: 1) We will determine how NOPR and NOPR -signaling mutants function in specific cells and dopaminergic neural circuits to control cocaine preference behavior using targeted viral rescue strategies, and behavioral models. Here we will employ viral-mediated cell type specific """"""""knock-in"""""""" gain-of-function experiments in mice, using wild-type and mutant receptors to determine how NOPR receptors function in dopaminergergic circuits to control cocaine preference in vivo. 2) In aim 2 we will use a combination of mouse genetics, anatomical techniques with tDtomato-reporter mice, and optogenetic approaches to dissect the role of nociceptin containing neurons on cocaine place preference, reward, and aversion behavior. Together, this project and the experiments described could provide novel and important information about nociceptin-NOPR system function in drug abuse behaviors.

Public Health Relevance

Achieving a more complete understanding of the receptors and signal transduction pathways in the mammalian brain is crucial for further development of effective therapeutic treatments and the identification of novel drug targets for addiction. The studies here have the potential to open new pharmacological avenues for targeting the nociceptin system for drug abuse.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21DA034929-01A1
Application #
8638251
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Sorensen, Roger
Project Start
2014-04-15
Project End
2016-03-31
Budget Start
2014-04-15
Budget End
2015-03-31
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Washington University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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Toll, Lawrence; Bruchas, Michael R; Calo', Girolamo et al. (2016) Nociceptin/Orphanin FQ Receptor Structure, Signaling, Ligands, Functions, and Interactions with Opioid Systems. Pharmacol Rev 68:419-57
Zhang, Nancy R; Planer, William; Siuda, Edward R et al. (2012) Serine 363 is required for nociceptin/orphanin FQ opioid receptor (NOPR) desensitization, internalization, and arrestin signaling. J Biol Chem 287:42019-30