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.
Bibliographical noteFunding 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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