Genetic behavioral screen identifies an orphan anti-opioid system

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.

Source: ScienceNOW - September 18, 2019 Category: Science Authors: Wang, D., Stoveken, H. M., Zucca, S., Dao, M., Orlandi, C., Song, C., Masuho, I., Johnston, C., Opperman, K. J., Giles, A. C., Gill, M. S., Lundquist, E. A., Grill, B., Martemyanov, K. A. Tags: Cell Biology, Neuroscience r-articles Source Type: news