Research Article

Genetic behavioral screen identifies an orphan anti-opioid system

See allHide authors and affiliations

Science  20 Sep 2019:
Vol. 365, Issue 6459, pp. 1267-1273
DOI: 10.1126/science.aau2078

You are currently viewing the abstract.

View Full Text

Log in to view the full text

Log in through your institution

Log in through your institution

Worms yield opioid receptor insight

The µ-opioid receptor (MOR) is the target of pain-reducing drugs, including morphine and the potent synthetic opioid fentanyl. Better understanding of the receptor system is needed to suppress potentially deadly side effects and manage addiction potential. Wang et al. used a screen in the worm Caenorhabditis elegans to find genes that influenced MOR function (see the Perspective by Mercer Lindsay and Scherrer). They found another receptor called GPR139, loss of which enhanced effects of morphine in mice but reduced withdrawal effects. GPR139 could be a target to improve safety or efficacy of opioid therapy.

Science, this issue p. 1267; see also p. 1246

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.

View Full Text