Pain management strategies that do not cause hazardous side effects like pleasure or addiction have proven elusive. Scientists have been working for decades to create medications that selectively activate one kind of opioid receptor to relieve pain while avoiding activating another type of opioid receptor associated to addiction. Unfortunately, such substances can create hallucinations, which is a separate unpleasant consequence. However, a recent study headed by Washington University School of Medicine in St. Louis has uncovered a potential pain management method that does not create addiction or activate the circuit that produces hallucinations.
The findings were published in the journal Nature on May 3rd.
Pain relievers like morphine and oxycodone, as well as illicit street narcotics like heroin and fentanyl, activate mu opioid receptors on nerve cells. These receptors reduce pain but also provide pleasure – the sensation of being high -, which adds to addiction. Another option is to target another opioid receptor known as the kappa opioid receptor. Scientists working on medications that solely target the kappa receptor have discovered that they successfully reduce pain, but they also cause additional adverse effects such as hallucinations.
Since 2002, scientists have been trying to learn how this small molecule causes hallucinations through kappa receptors. 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.”
Tao Che, PhD, principal investigator, assistant professor of anesthesiology
Researchers from Washington University School of Medicine’s Center for Clinical Pharmacology and the University of Health Sciences & Pharmacy in St. Louis have uncovered the probable processes underlying such hallucinations, with the objective of producing painkillers without this side effect. They discovered how a natural chemical linked to the salvia plant preferentially attaches just to the kappa receptor yet creates hallucinations using electron microscopes.
Creating novel medications that target these alternative kappa receptor binding locations might alleviate pain without the addiction difficulties associated with older opioids or the hallucinations associated with present therapies that preferentially target the kappa opioid receptor.
According to Che, targeting the kappa receptor to block pain without inducing hallucinations would be a significant step forward because opioid medicines that interact with the mu opioid receptor have contributed to the current opioid epidemic, which is expected to result in more than 100,000 overdose fatalities in the United States by 2021.
“Opioids, particularly synthetic opioids like fentanyl, have caused far too many overdose deaths,” Che added. “There is no doubt that we require safer pain relievers.”
Che’s team discovered that a family of signaling proteins known as G proteins allow the kappa opioid receptor to activate numerous distinct pathways, lead by first author Jianming Han, PhD, a postdoctoral research assistant in Che’s group.
“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,” Han explained. “By learning how each of the proteins binds to the kappa receptor, we expect to find ways to activate that receptor without causing hallucinations.”
Until today, the function of G proteins, specifically the protein that triggers the hallucination pathway, was mostly unknown.
“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,” Che explained. “We discovered that hallucinogenic drugs preferentially activate one specific G protein but not other, related G proteins, implying that beneficial effects like pain relief can be distinguished from side effects like hallucinations.” As a result, we anticipate that treatments that stimulate the kappa receptor to eliminate pain without simultaneously activating the particular pathway that produces hallucinations will be developed.”
Erin Balsa is a highly skilled and knowledgeable health journalist with a passion for educating the public on important health and wellness topics. With extensive experience in both traditional and digital media, Erin has established herself as a trusted voice in the field.