Researchers at The Scripps Research Institute in Florida recently published a study in the journal Science describing a newly discovered biological system that manages how cells respond to exposure to opioids.
In 2017, the U.S. Department of Health and Human Services (HHS) declared the opioid epidemic a public health emergency. Every year about 11.4 million people misuse prescription opioids, and more than 130 people died that year every day from opioid-related drug overdoses.
Research into non-opioid pain medications and into treatments for opioid overdoses has accelerated. Researchers at The Scripps Research Institute in Florida recently published a study in the journal Science describing a newly discovered biological system that manages how cells respond to exposure to opioids. It has the potential to improve the safety of this class of drugs.
Their research utilized the nematode C. elegans, which was engineered to express the mammalian surface receptor µ (mu) opioid receptor (MOR). It’s not normally found in nematode DNA, so this model allows the transgenic animals to respond to opioids like morphine and fentanyl. The science team, led by Kirill Martemyanov and Brock Grill, exposed the worms to mutagens and chose the ones with abnormal responses to opioids. They then sequenced the DNA and utilized CRISPR gene editing to isolate the genes responsible for the responses.
They eventually narrowed in on the FRPR-13 receptor in the worms, conserved in all animals, and is called GPR139 in mammals. This particular receptor is not well understood, and its role is unknown. However, more experiments in mice found that GPR139 was expressed on the same nerve cells as MOR and counteracted the effect of opioids.
Working with mice addicted to opioids, they injected drugs that activated GPR139. The mice stopped taking the drug. In reverse experiments, by eliminating GPR139, it enhanced the pain-killing effects of the opioids.
In addition, mice modified to not have GPR139 had very minor withdrawal symptoms after chronic exposure to opioids.
“A lot of addicts know that if they stop using, they are going to deal with anxiety, nausea, tremor and they are going to be in a lot of pain,” Grill stated. “That probably has a very negative impact on people wanting to go into rehab.”
These new insights into the biological mechanisms of opioid behavior and addictive response may point the way for new classes of opioids that are less addictive or to effective treatments for opioid addiction.
“Forward genetics—unbiased genetic discovery—has never been applied to probing an opioid receptor like this,” Grill stated. “The opioid epidemic is a huge problem and we don’t have good solutions. 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.”
Currently, the top makers of opioids are tangled in thousands of lawsuits and government investigations into their aggressive marketing practices that attributed to the abuse of opioids. One of the companies most prominent in these efforts is Purdue Pharma, manufacturer of OxyContin. Others include Bristol-Myers Squibb, which produces Percocet, and generic drugmaker Apotex.
In April, Purdue settled a lawsuit in Oklahoma for $270 million. Other opioid manufacturers involved in lawsuits related to opioids include Teva Pharmaceutical and Johnson & Johnson. Purdue alone is the subject of more than 1,600 lawsuits. The state of Massachusetts has alleged that Purdue is to blame for 670 opioid-related deaths in the state since 2009.
Earlier this year, the U.S. government filed criminal charges against executives at the Rochester Drug Co-Operative, Inc. (RDC), one of the 10 biggest pharmaceutical distributors in the U.S. for the part they played in distributing opioids. According to the federal charges, from 2012 through March 2017, the company violated federal narcotics laws by distributing these opioids to pharmacy customers when it knew they were being sold and used illicitly.
