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Science. 2019 Aug 15. pii: eaau2078. doi: 10.1126/science.aau2078. [Epub ahead of print]

Genetic behavioral screen identifies an orphan anti-opioid system.

Author information

1
Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA.
2
Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL 33458, USA.
3
Department of Molecular Biosciences, The University of Kansas, Lawrence, KS 66045, USA.
4
Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA. kirill@scripps.edu bgrill@scripps.edu.

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 C. 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 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 GPCR signaling principles.

PMID:
31416932
DOI:
10.1126/science.aau2078

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