Genetic behavioral screen identifies an orphan anti-opioid system.
Science
; 365(6459): 1267-1273, 2019 09 20.
Article
en En
| MEDLINE
| ID: mdl-31416932
ABSTRACT
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.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Conducta Animal
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Caenorhabditis elegans
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Receptores Opioides mu
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Receptores Acoplados a Proteínas G
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Receptores Nucleares Huérfanos
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Proteínas del Tejido Nervioso
Límite:
Animals
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Female
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Humans
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Male
Idioma:
En
Revista:
Science
Año:
2019
Tipo del documento:
Article
País de afiliación:
Estados Unidos