Strategies to treat pain without triggering dangerous side effects like euphoria and addiction have proven elusive. For decades, scientists have tried to develop drugs that selectively activate one type of opioid receptor to treat pain without activating another type of addiction-related opioid receptor. Unfortunately, those compounds can cause a different unwanted effect: hallucinations. But a new study led by the Washington University School of Medicine in St. Louis has identified a potential pathway to pain relief that doesn’t trigger addiction or activate the pathway that causes hallucinations.
The research is published May 3 in the journal Nature.
Pain relievers like morphine and oxycodone, as well as illegal street drugs like heroin and fentanyl, activate what are known as mu opioid receptors on nerve cells. Those receptors relieve pain, but they also cause euphoria, the feeling of being high, and that feeling contributes to addiction. An alternative strategy is to target another opioid receptor, called the kappa opioid receptor. Scientists trying to make drugs that target only the kappa receptor have found that they also effectively relieve pain, but they may be associated with other side effects, such as hallucinations.
Researchers at the Center for Clinical Pharmacology at the Washington University School of Medicine and the University of Pharmacy and Health Sciences, also in St. Louis, have identified the potential mechanisms behind such hallucinations, with the goal of developing pain relievers without this side effect. Using electron microscopes, they identified the way in which a natural compound related to the sage plant selectively binds only to the kappa receptor but then causes hallucinations.
“Since 2002, scientists have been trying to learn how this small molecule causes hallucinations through kappa receptors,” said lead investigator Tao Che, PhD, an assistant professor of anesthesiology. “We determined how it binds to the receptor and activates potential hallucinogenic pathways, but also found that other binding sites on the kappa receptor do not cause hallucinations.”
Developing new drugs to target these other kappa receptor binding sites may relieve pain without the addictive problems associated with older opioids or the hallucinations associated with existing drugs that selectively target the kappa opioid receptor.
Targeting the kappa receptor to block pain without hallucinations would be an important step forward, according to Che, because opioid drugs that interact with the mu opioid receptor have led to the current opioid epidemic, which has caused more than 100,000 overdose deaths in USA in 2021.
“Opioids, especially synthetic opioids like fentanyl, have contributed to far too many overdose deaths,” Che said. “There is no question that we need safer drugs to relieve pain.”
Che’s team, led by first author Jianming Han, PhD, a postdoctoral research associate in Che’s lab, 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 while they are very similar to one another, the differences between the proteins may help explain why some compounds can cause side effects such as hallucinations,” Han said. “By learning how each of the protein binds to the kappa receptor, we hope to find ways to activate that receptor without causing hallucinations.”
The function of G proteins has been largely unclear until now, particularly the protein that activates the pathway that leads to hallucinations.
“All of these proteins are similar to each other, but the specific subtypes of proteins that bind to the kappa receptor determine which pathways will be activated,” Che said. “We found that hallucinogenic drugs can preferentially activate a 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. Therefore, We hope it will be possible to find therapies that activate the kappa receptor to kill pain without also activating the specific pathway that causes hallucinations.”
The study was funded with support from the National Institute of General Medical Sciences and the National Institute of Neurological Disorders and Stroke at the National Institutes of Health (NIH). Concession numbers: R35 GM143061 and R01 NS099341.
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