Narcotic analgesics (i.e. opiates such as morphine) and endogenous opioid peptides bind to the three types of opioid receptors (mu, delta, kappa) with varying affinities and activate these receptors to different extents. Opioid receptor function is modulated by multiple mechanisms;the long-term objective of the project is to understand the contribution of these mechanisms to receptor activity. This application is focused on exploring a recently recognized mechanism of 'receptor dimerization/oligomerization'in modulating opioid receptor function. We and others have previously shown that mu receptors dimerize with delta receptors and this changes receptor properties. Recently we generated mu-delta heterodimer-selective antibodies. Using these we have found that levels of mu-delta heterodimers can be differentially regulated by opiates in vivo. The functional consequences of this regulation and the molecular mechanisms involved are not known. In this application we propose studies to directly address this important question.
Specific Aim # 1 is to examine the novel signaling pathways activated by the mu-delta heterodimer using classic biochemical techniques.
Aim # 2 is to investigate the distinct maturation/assembly and trafficking properties of the heterodimer using cell biological and imaging techniques.
Aim #3 is to study the distribution and regulation of the heterodimer by morphine in vivo using immunohistochemical techniques.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Molecular Neuropharmacology and Signaling Study Section (MNPS)
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Wu, Da-Yu
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Icahn School of Medicine at Mount Sinai
Schools of Medicine
New York
United States
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Lueptow, Lindsay M; Devi, Lakshmi A; Fakira, Amanda K (2018) Targeting the Recently Deorphanized Receptor GPR83 for the Treatment of Immunological, Neuroendocrine and Neuropsychiatric Disorders. Prog Mol Biol Transl Sci 159:1-25
Fricker, Lloyd D; Devi, Lakshmi A (2018) Orphan neuropeptides and receptors: Novel therapeutic targets. Pharmacol Ther 185:26-33
Margolis, Elyssa B; Fujita, Wakako; Devi, Lakshmi A et al. (2017) Two delta opioid receptor subtypes are functional in single ventral tegmental area neurons, and can interact with the mu opioid receptor. Neuropharmacology 123:420-432
Reckziegel, PatrĂ­cia; Festuccia, William T; Britto, Luiz R G et al. (2017) A novel peptide that improves metabolic parameters without adverse central nervous system effects. Sci Rep 7:14781
Heimann, Andrea S; Gupta, Achla; Gomes, Ivone et al. (2017) Generation of G protein-coupled receptor antibodies differentially sensitive to conformational states. PLoS One 12:e0187306
Gomes, Ivone; Sierra, Salvador; Devi, Lakshmi A (2016) Detection of Receptor Heteromerization Using In Situ Proximity Ligation Assay. Curr Protoc Pharmacol 75:2.16.1-2.16.31
Gomes, Ivone; Bobeck, Erin N; Margolis, Elyssa B et al. (2016) Identification of GPR83 as the receptor for the neuroendocrine peptide PEN. Sci Signal 9:ra43
Wardman, Jonathan H; Gomes, Ivone; Bobeck, Erin N et al. (2016) Identification of a small-molecule ligand that activates the neuropeptide receptor GPR171 and increases food intake. Sci Signal 9:ra55
Gupta, Achla; Gomes, Ivone; Bobeck, Erin N et al. (2016) Collybolide is a novel biased agonist of ?-opioid receptors with potent antipruritic activity. Proc Natl Acad Sci U S A 113:6041-6
Gomes, Ivone; Ayoub, Mohammed Akli; Fujita, Wakako et al. (2016) G Protein-Coupled Receptor Heteromers. Annu Rev Pharmacol Toxicol 56:403-25

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