Abstract
Kappa opioid receptor (KOR) agonists possess adverse dysphoric and psychotomimetic effects, thus limiting their applications as non-addictive anti-pruritic and analgesic agents. Here, we showed that protein kinase C (PKC) inhibition preserved the beneficial antinociceptive and antipruritic effects of KOR agonists, but attenuated the adverse condition placed aversion (CPA), sedation, and motor incoordination in mice. Using a large-scale mass spectrometry-based phosphoproteomics of KOR-mediated signaling in the mouse brain, we observed PKC-dependent modulation of G protein-coupled receptor kinases and Wnt pathways at 5 min; stress signaling, cytoskeleton, mTOR signaling and receptor phosphorylation, including cannabinoid receptor CB1 at 30 min. We further demonstrated that inhibition of CB1 attenuated KOR-mediated CPA. Our results demonstrated the feasibility of in vivo biochemical dissection of signaling pathways that lead to side effects.
Keywords:
CB1; Phosphoproteomics; Protein kinase C; Wnt; mTOR; κ opioid receptor.
Copyright © 2020 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / pharmacology
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Animals
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Avoidance Learning
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G-Protein-Coupled Receptor Kinases
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Male
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Mice
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Motor Activity / drug effects
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Phosphoproteins
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Phosphorylation
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Protein Kinase C / drug effects
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Protein Kinase C / genetics*
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Protein Kinase C / radiation effects
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Protein Kinase Inhibitors
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Proteomics
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Receptor, Cannabinoid, CB1 / drug effects
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Receptors, G-Protein-Coupled / drug effects
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Receptors, Opioid, kappa / drug effects
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Receptors, Opioid, kappa / genetics*
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Receptors, Opioid, kappa / radiation effects
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Signal Transduction / drug effects*
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TOR Serine-Threonine Kinases / drug effects
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Wnt Signaling Pathway / drug effects
Substances
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Phosphoproteins
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Protein Kinase Inhibitors
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Receptor, Cannabinoid, CB1
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Receptors, G-Protein-Coupled
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Receptors, Opioid, kappa
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3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer
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mTOR protein, mouse
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TOR Serine-Threonine Kinases
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Protein Kinase C
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G-Protein-Coupled Receptor Kinases