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How nematode worms could inspire safer opioid use

Roundworms helped scientists at the Scripps Research Institute discover that GPR139 could be a useful target for increasing opioid safety. (Wikimedia Commons)

Pain-relieving opioids have come under fire lately because of their addictive properties and potential for abuse. Scientists at the Scripps Research Institute went looking for clues to reduce opioids’ toxic effects, and, in so doing, built a research platform based on nematodes. That research led them to a rare receptor they say might one day make opioid use safer.

The nematode that the Scripps Research team used is called Caenorhabditis elegans. These soil worms have an opioidlike system that controls feeding behavior and responses to harmful stimuli. Using the worms, the scientists identified GPR139 as an inhibitor of opioid-induced signaling. The receptor—which belongs to the big G protein-coupled receptor (GPCR) family—makes the worms less sensitive to opioid side effects, they reported in a study published in Science.

Opioids such as morphine and fentanyl target the mu-opioid receptors (MORs) to achieve pain management. To study the behavior of the receptors, the Scripps researchers genetically modified C. elegans so it would express mammalian MOR in its nervous system.

About 900 of the mutations they induced produced abnormal sensitivity to both morphine and fentanyl. Further analysis led them to an understudied orphan GPCR called FRPR-13. They zeroed in on the mammalian analog GPR139 because it is expressed in the central nervous system rather than in the “periphery,” they said in the study.

Turns out, GPR139 can exert inhibitory effects on MOR signaling. Removing GPR139 in mice enhanced the ability of morphine to inhibit neuronal firing by reducing levels of MOR, the scientists observed. That translated into a significantly increased analgesic effect in the GPR139 knockout animals.

What’s more, when a chronic morphine supply was cut off, the mice lacking GPR139 had fewer withdrawal symptoms than did their normal counterparts. The team attributed the difference to changes in the firing rate of neurons in a part of brain called locus coeruleus, which is involved in opioid withdrawal. Excruciating withdrawal symptoms such as nausea, cravings and anxiety often occur in people when they stop taking opioids—a significant barrier for patients looking to overcome addiction.

Now that opioid overuse has been identified as a public health crisis in the U.S., scientists are looking for new ways to fight dependence while at the same time preserving the drugs’ pain-killing effects. Researchers at Duke University and Villanova University recently found that Allergan’s failed antidepressant rapastinel might help manage withdrawal symptoms, for example. And researchers from the Walter Reed Army Institute of Research and the National Institutes of Health who are developing a heroin vaccine have reported that the drug can produce antibodies that block heroin from exerting euphoric effects in the brain.

The Scripps researchers hope their discovery will spark new ideas for increasing opioid safety. “Our results suggest that GPR139 could potentially be exploited pharmacologically for increasing safety and efficacy of opioid pharmacotherapy,” the authors said in the study.