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Genetic behavioral screen identifies an orphan anti-opioid system
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Journal Article
Genetic behavioral screen identifies an orphan anti-opioid system
2019
Overview
Opioids target the μ-opioid receptor (MOR) to produce unrivaled pain management, but their addictive properties can lead to severe abuse. We developed a whole-animal behavioral platform for unbiased discovery of genes influencing opioid responsiveness. Using forward genetics in Caenorhabditis elegans, we identified a conserved orphan receptor, GPR139, with anti-opioid activity. GPR139 is coexpressed with MOR in opioid-sensitive brain circuits, binds to MOR, and inhibits signaling to heterotrimeric guanine nucleotide–binding proteins (G proteins). Deletion of GPR139 in mice enhanced opioid-induced inhibition of neuronal firing to modulate morphine-induced analgesia, reward, and withdrawal. Thus, GPR139 could be a useful target for increasing opioid safety. These results also demonstrate the potential of C. elegans as a scalable platform for genetic discovery of G protein–coupled receptor signaling principles.
Publisher
American Association for the Advancement of Science,The American Association for the Advancement of Science
Subject
/ Animals
/ Animals, Genetically Modified
/ Caenorhabditis elegans - genetics
/ Deletion
/ Female
/ Genes
/ Genetics
/ Humans
/ Male
/ Mice
/ Morphine
/ Nerve Tissue Proteins - genetics
/ Opioids
/ Orphan Nuclear Receptors - genetics
/ Pain
/ Proteins
/ Receptors, G-Protein-Coupled - genetics
/ Receptors, Opioid, mu - genetics
/ Safety
