Targeting the opioid receptor pathway could treat pain without addiction or hallucinations.
Researchers have discovered a new approach to developing painkillers that do not cause addiction or hallucinations by targeting specific binding sites on the kappa opioid receptor and understanding the interaction of G proteins bound to the receptor. This could lead to safer painkillers.
Strategies to treat pain without triggering dangerous side effects such as 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, these compounds can cause another side effect: hallucinations. But a new study from Washington University School of Medicine in St. Louis has identified a potential pain relief pathway that doesn’t trigger addiction or activate the pathway that causes hallucinations.
The research was published May 3 in the journal Nature.
Pain relievers like morphine and oxycodone, as well as street drugs like heroin and
Researchers from the Center for Clinical Pharmacology at Washington University School of Medicine and the University of Health Sciences & Pharmacy, also in St. Louis, have identified potential mechanisms behind such hallucinations, with the goal of developing painkillers without this side effect. Using electron microscopes, they identified how a natural compound related to the salvia plant selectively binds only to the kappa receptor but then causes hallucinations.
“Since 2002, scientists have been trying to understand how this small molecule causes hallucinations via kappa receptors,” said lead researcher Tao Che, PhD, assistant professor of anesthesiology. “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 do not lead to hallucinations.”
Developing new drugs to target these other kappa receptor binding sites can relieve pain without the addiction 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 a big step forward, Che says, because opioid drugs that interact with the mu-opioid receptor have led to the current opioid epidemic, causing more than 100,000 deaths. by overdose in the United States in 2021. .
“Opioids, especially synthetic opioids like fentanyl, have contributed to far too many overdose deaths,” Che said. “There is no doubt that we need safer pain medications.”
Che’s team, led by first author Jianming Han, PhD, a postdoctoral research associate in Che’s lab, found 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 certain compounds can cause side effects such as hallucinations,” Han said. . “By learning how each of the proteins binds to the kappa receptor, we hope to find ways to activate this receptor without causing hallucinations.”
The function of G proteins was until now largely unknown, in particular the protein that activates the pathway linked to hallucinations.
“All of these proteins are similar to each other, but the specific protein subtypes 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. We therefore expect that it will be possible to find therapies that activate the kappa receptor to kill pain without also activating the specific pathway that causes hallucinations.
Reference: “Selectivity of Ligands and G Proteins in the κ-opioid Receptor” by Jianming Han, Jingying Zhang, Antonina L. Nazarova, Sarah M. Bernhard, Brian E. Krumm, Lei Zhao, Jordy Homing Lam, Vipin A. Rangari , 2005; Susruta Majumdar, David E. Nichols, Vsevolod Katritch, Peng Yuan, Jonathan F. Fay, and Tao Che, May 3 Nature.
The study was funded with support from the National Institute of General Medical Sciences and the National Institute of Neurological Disorders and Stroke of the