For decades, strategies to treat pain without triggering potentially dangerous side effects such as euphoria and addiction have proven elusive. Although scientists have recently managed to develop painkillers that selectively activate one type of opioid receptor in order to relieve pain while not activating another receptor linked to addiction, these new compounds were found to have yet another unwanted side effect: hallucinations.
Now, a team of researchers led by the Washington University in St. Louis (WUSTL) has identified a potential route to effective pain relief that would neither lead to addiction nor cause hallucinations.
Painkillers such as oxycodone or morphine, as well as illegal drugs like heroin or fentanyl, work by activating the so-called “mu receptors” on nerve cells. While these receptors can relieve pain, they also cause feelings of euphoria, and easily lead to addiction.
To sidestep these issues, experts devised an alternative strategy to target another opioid receptor known as the “kappa receptor.” Unfortunately, drugs designed to target this receptor were found to cause hallucinations.
In the current study – published in the journal Nature – researchers managed to identify the potential mechanisms causing hallucinations, which can be an important step forward in designing pain treatments without this side effect. By using electron microscopes, they discovered that a natural compound related to the salvia plant selectively binds to the kappa receptor, leading to hallucinations.
“Since 2002, scientists have been trying to learn how this small molecule causes hallucinations through kappa receptors,” said senior author Tao Che, an assistant professor of Anesthesiology at WUSTL. “We determined how it binds to the receptor and activates potential hallucinogenic pathways, but we also found that other binding sites on the kappa receptor don’t lead to hallucinations.”
Che and team discovered that a class of signaling proteins called “G proteins” cause the kappa opioid receptor to activate several different pathways.
“There are seven G proteins linked to the kappa receptor, and although they are very similar to each other, the differences between the proteins may help explain why some compounds can cause side effects such as hallucinations,” explained lead author Jianming Han, a postdoctoral researcher in Che’s laboratory. “By learning how each of the proteins binds to the kappa receptor, we expect to find ways to activate that receptor without causing hallucinations.”
“All of these proteins are similar to one another, but the specific protein subtypes that bind to the kappa receptor determine which pathways will be activated. We have found that the hallucinogenic drugs can preferentially activate one specific G protein but not other, related G proteins, suggesting that beneficial effects such as pain relief can be separated from side effects such as hallucinations. So we expect it will be possible to find therapeutics that activate the kappa receptor to kill pain without also activating the specific pathway that causes hallucinations,” Che added.
Since opioid drugs interacting with the mu receptor are the main cause behind the current opioid epidemic, which led to over 100,000 overdose deaths in the U.S. in 2021, targeting the kappa receptor to relieve pain without causing hallucinations would be a critical step forward to design safer, non-addictive painkillers.