Genetic behavioral screen identifies an orphan anti-opioid system

Dandan Wang; Hannah M. Stoveken; Stefano Zucca; Maria Dao; Cesare Orlandi; Chenghui Song; Ikuo Masuho; Caitlin Johnston; Karla J. Opperman; Andrew C. Giles; Matthew S. Gill; Erik A. Lundquist; Brock Grill; Kirill A. Martemyanov

doi:10.1126/science.aau2078

Genetic behavioral screen identifies an orphan anti-opioid system

Dandan Wang, Hannah M. Stoveken, Stefano Zucca, Maria Dao, Cesare Orlandi, Chenghui Song, Ikuo Masuho, Caitlin Johnston, Karla J. Opperman, Andrew C. Giles, Matthew S. Gill, Erik A. Lundquist, Brock Grill, Kirill A. Martemyanov

Research output: Contribution to journal › Article › peer-review

32 Scopus citations

Abstract

Opioids target the m-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.

Original language	English (US)
Pages (from-to)	1267-1273
Number of pages	7
Journal	Science
Volume	365
Issue number	6459
DOIs	https://doi.org/10.1126/science.aau2078
State	Published - Sep 20 2019
Externally published	Yes

Bibliographical note

Funding Information:
We thank N. Martemyanova for producing and maintaining mice examined in this study and members of the Grill and Martemyanov labs for valuable input. We thank T. Bannister and X. Pan for providing JNJ-63533054, B. Ackley for helpful discussions, and Max Planck Florida Institutes? microscopy core facility. Knockout mice were made by the KOMP Repository (www.komp.org) at the University of California Davis (U42RR024244). This work was supported by an NIH Cutting Edge Basic Research Award (R21DA040406) to B.G. and K.A.M., DA036596 to K.A.M., and an NIH Center of Biomedical Research Excellence Grant (P20GM103638) to University of Kansas Genome Sequencing Core.

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Copyright © 2019 The Authors,

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title = "Genetic behavioral screen identifies an orphan anti-opioid system",

abstract = "Opioids target the m-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.",

author = "Dandan Wang and Stoveken, {Hannah M.} and Stefano Zucca and Maria Dao and Cesare Orlandi and Chenghui Song and Ikuo Masuho and Caitlin Johnston and Opperman, {Karla J.} and Giles, {Andrew C.} and Gill, {Matthew S.} and Lundquist, {Erik A.} and Brock Grill and Martemyanov, {Kirill A.}",

note = "Funding Information: We thank N. Martemyanova for producing and maintaining mice examined in this study and members of the Grill and Martemyanov labs for valuable input. We thank T. Bannister and X. Pan for providing JNJ-63533054, B. Ackley for helpful discussions, and Max Planck Florida Institutes? microscopy core facility. Knockout mice were made by the KOMP Repository (www.komp.org) at the University of California Davis (U42RR024244). This work was supported by an NIH Cutting Edge Basic Research Award (R21DA040406) to B.G. and K.A.M., DA036596 to K.A.M., and an NIH Center of Biomedical Research Excellence Grant (P20GM103638) to University of Kansas Genome Sequencing Core. Publisher Copyright: Copyright {\textcopyright} 2019 The Authors,",

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AU - Wang, Dandan

AU - Stoveken, Hannah M.

AU - Zucca, Stefano

AU - Dao, Maria

AU - Orlandi, Cesare

AU - Song, Chenghui

AU - Masuho, Ikuo

AU - Johnston, Caitlin

AU - Opperman, Karla J.

AU - Giles, Andrew C.

AU - Gill, Matthew S.

AU - Lundquist, Erik A.

AU - Grill, Brock

AU - Martemyanov, Kirill A.

N1 - Funding Information: We thank N. Martemyanova for producing and maintaining mice examined in this study and members of the Grill and Martemyanov labs for valuable input. We thank T. Bannister and X. Pan for providing JNJ-63533054, B. Ackley for helpful discussions, and Max Planck Florida Institutes? microscopy core facility. Knockout mice were made by the KOMP Repository (www.komp.org) at the University of California Davis (U42RR024244). This work was supported by an NIH Cutting Edge Basic Research Award (R21DA040406) to B.G. and K.A.M., DA036596 to K.A.M., and an NIH Center of Biomedical Research Excellence Grant (P20GM103638) to University of Kansas Genome Sequencing Core. Publisher Copyright: Copyright © 2019 The Authors,

PY - 2019/9/20

Y1 - 2019/9/20

N2 - Opioids target the m-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.

AB - Opioids target the m-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.

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Genetic behavioral screen identifies an orphan anti-opioid system

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