Anti-Opioid Pathway Discovered via Forward Genetics Approach with C. elegans

Scientists at Scripps Research in Florida report that they have discovered a biological system that manages cells response to opioid drug exposure. The team said its discovery offers new ideas for improving the safety of the one of the most effective, and most abused, group of pain medications. In a paper Genetic behavioral screen identifies an orphan anti-opioid system published in Science, lead authors Kirill Martemyanov, PhD, and Brock Grill, PhD, described how they designed and implemented a new approach using a nematode worm for decoding the genetic network that controls actions of opioids in a nervous system. “Opioids target 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,” the investigators wrote. “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.”