Studying mutant worms has led to the discovery of a receptor that reduces sensitivity to opioid side effects in these organisms. The work implicates the understudied GPR139 receptor in the toxic effect of these painkillers; the authors say GPR139 could be a useful target for increasing opioid safety. Despite side effects like addiction and dependency, opioids such as morphine and fentanyl remain the standard of care for pain relief. These drugs target the mu opioid peptide receptor (MOR). A better understanding of the MOR receptor system is needed to avoid problems with side effects and addiction, though identifying molecular mechanisms that regulate opioid MOR receptor activity has been challenging. Here, researchers led by Dandan Wang developed a platform that would allow for the genetic discovery of proteins that modified MOR signaling. As part of their work, they engineered mutations in about 2,500 Caenorhabditis elegans nematodes. By studying these and also control nematodes, they identified hundreds of organisms with increased sensitivity to opioids. In experiments attempting to reduce this sensitivity, the researchers uncovered a regulator of mu opioid peptide receptor signaling, GPR139, that made the worms less sensitive to opioid side effects. In further studies in mice, deletion of GPR139 enhanced morphine's analgesic effect but reduced withdrawal effects. "Our results suggest that GPR139 could potentially be exploited pharmacologically for increasing safety and efficacy of opioid pharmacotherapy," the authors say.