In an advancement for developing safer painkillers, scientists have solved the crystal structure of one of the key brain receptors activated by opioids, which is what gives them their pain-relieving power. With this new understanding, they’ve developed a drug-like compound that activates only that receptor, which could lead to medications that treat pain without the dangerous side effects of today’s opioid meds.
The study, conducted by researchers at the University of North Carolina School of Medicine and published in the journal Cell, sought to isolate opioids’ analgesic effects. Though they’re potent painkillers, they can have serious side effects including nausea, numbness, and constipation, and can produce anxiety and hallucinations. Most crucially, they can create severe dependency, and, during an overdose, can slow breathing so much that people stop breathing altogether and can die. Some people using opioid painkillers (whether prescribed to them or not) become addicted and transition to heroin, another opioid drug, which can slow breathing the same way.
"Tens of thousands people who take opioids die every year, and so we need safer and more effective drugs for treating pain and related conditions," Bryan Roth, a professor of pharmacology at UNC-Chapel Hill and senior author on the paper, said in a statement.
The Centers for Disease Control and Prevention says that, between 1999 and 2015, more than 183,000 people have died in the United States from overdoses related to prescription opioids, including more than 15,000 deaths in 2015 alone. When that’s broadened to all opioids including heroin, there were 33,000 overdose deaths in 2015 and 42,000 in 2016.
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Part of why these drugs have a wide range of side effects is because most opioids bond to several opioid receptors, which are proteins on the surface of brain cells. Figuring out which bonds relieve pain and which produce side effects gets scientists one step closer to creating a less-dangerous painkiller. Thus far that’s been a challenge, because opioid receptors are small and delicate, making them harder to experiment on. But the researchers honed in on one promising receptor, the kappa opioid receptor (KOR), sussing out the structure that activates it.
"One of the big ideas is to target KORs because the few drugs that bind to it don't lead to addiction or cause death due to overdose,” Roth said. Those side effects, he explained, mainly come from another receptor, the mu opioid receptor. His team figured out the kappa receptor’s structure by taking 3D images of it in its active state and then created a compound that only activated it, not the other receptors like mu.
Unlocking the kappa receptor removes a big hurdle for researchers, who can now make pain relievers with carefully targeted effects. "To create better opioids, we need to know the structure of their receptors," Roth said. "Until recently, this was impossible. But now we know the structure of the activated kappa opioid receptor. And we showed we can actually use the structure to make a drug-like compound with better properties than current opioids."
The kappa receptor is linked to its own side effects like hallucination but the team believes they could avoid that by targeting certain parts of the receptor. Still, it’s not clear if drugs that only target the kappa receptor would be as effective at relieving pain as drugs that target multiple receptors. Roth told CNBC the structure will be available for anyone to download so other researchers and drug companies can work on it, too.
Possible treatments will need to undergo extensive testing for safety and effectiveness, first in animals then in humans, so they’re years away from being available. Right now, though, the new research has opened up a world of potential.