A path to prevent addiction?

Scripps Research finds an anti-opioid pathway

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JUPITER, Fla.—A team at Scripps Research in Florida has announced the discovery of a biological system that manages cells’ response to opioid drug exposure, an unexpected discovery that offers new ideas for improving the safety of pain medications.
In a paper entitled “Genetic behavioral screen identifies an orphan anti-opioid receptor,” lead authors Drs. Kirill Martemyanov and Brock Grill described how they designed and implemented a new approach for decoding the genetic network that controls actions of opioids in a nervous system. The study appears online in Science.
“A study like this makes it clear that even though we may think we know everything there is to know about the opioid response, we’re actually just scratching the surface,” Martemyanov said.
“Forward genetics—unbiased genetic discovery—has never been applied to probing an opioid receptor like this,” Grill added. “This type of approach can bring a whole new array of targets and a new way of thinking about and going after an old problem.”
Researchers used the nematode Caenorhabditis elegans to discover something surprising about one of the most-studied drug receptors. Their system engineered C. elegans to express the mammalian surface receptor for painkilling drugs, the μ (mu) opioid receptor (MOR). The receptor is not normally found in the worms’ DNA, and adding it made the transgenic animals respond to opioids like morphine and fentanyl.
The researchers then exposed the worms to mutagens and selected the ones with abnormal responses to opioids. Whole-genome sequencing and CRISPR engineering was used to pinpoint the genes responsible for those aberrant responses.
According to Grill, an associate professor in the Department of Neuroscience at the Scripps Research Florida campus, “To screen opioid affects behaviorally, you need several things worms bring to the table: 1) A small animal, so you can screen hundreds of animals simultaneously for effects of opioids on behavior; 2) An animal with a powerful, comprehensive genetic toolkit—that’s C. elegans; 3) An animal with a very short generation time, to make screening and genetics as fast as possible—C. elegans has a two- to three-day life cycle.
“Overall, this discovery is simply not possible without C. elegans. I think this shows everyone in America and the world that one of the smallest organisms on the planet with a nervous system could hold the key to solving many unmet biomedical needs.”
The work ultimately led the researchers to the worms’ FRPR-13 receptor, which is conserved in all animals and known as GPR139 in mammals. It is considered an orphan G protein-coupled receptor with poorly understood biology and an unknown role in physiology. Further studies in mice showed that GPR139 was expressed on the same neurons as MOR and counteracted the effects of opioids on neuronal firing.
“We mutated hundreds of thousands of worms. The FRPR-13 mutant was a single animal that had a faster response to opioids and lost that response quicker,” states Grill. “Our translational study clearly shows this is an anti-opioid system, but the biological role of FRPR-13 and GPR139 under normal physiological conditions remain unknown.”
When researchers administered drugs that activate GPR139, mice dependent on opioid intake stopped taking the drug. Conversely, genetic elimination of GPR139 augmented the pain-killing effects of opioids. The genetically modified mice lacking GPR139 also showed something remarkable—they showed very minimal withdrawal symptoms following chronic exposure to opioids.
Opioids like fentanyl, Vicodin, OxyContin and morphine are highly effective at blunting severe pain. Prolonged use can create tolerance and dependence, and excessive use can result in overdose, which leads to a search for a better way to control pain. Withdrawal symptoms usually set in upon the discontinuation of opioids following prolonged use. This discovery could point a way toward lessening the suffering associated with withdrawal.
The discovery of GPR139 also offers a new target for drug development aimed at making opiate therapies safer, Martemyanov added. Grill, Martemyanov and first author Dr. Dandan Wang noted that they are hopeful that the discovery will lead to a new generation of pain medications with less potential for abuse and overdose.
“There are several possibilities,” Grill explains. “A drug (that does not exist right now) that blocks GPR139 would theoretically make lower doses of opioids capable of killing pain. This could increase the therapeutic window for opioid use. We showed in mice that drugs activating GPR139 can prevent opioid self-administration. So, it’s possible drugs that activate GPR139 could help addicts reduce drug taking or seeking.”
“Finally, we had the unexpected discovery that loss of GPR139 blocks all withdrawal symptoms from chronic opioid exposure. This suggests that a drug that inhibits GPR139 might be a powerful treatment for opioid withdrawal symptoms. For example, during rehabilitation, addicts try and stop using opioids—which triggers withdrawal symptoms that are painful and problematic: body weight loss, anxiety, diarrhea, etc. It is possible a drug that inhibits GPR139 would block these withdrawal symptoms and make drug rehab easier to enter and ultimately more effective,” he points out.
When asked if he thinks researchers will be able to build on the GPR139 research to help create safer opiates and/or alternative pain therapies with a smaller risk of dependence or addiction, Grill concludes, “We hope so, but there is still a long way to go.”

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