A new study shows a potential route to pain relief that neither triggers addiction nor activates the pathway that causes hallucinations.
Washington University School of Medicine in St. Louis leads breakthrough research, published in Nature on May 3, uncovering a promising approach to pain relief.
For years, scientists have grappled with finding strategies to treat pain without triggering dangerous side effects like addiction and euphoria.
While previous attempts focused on selectively activating certain opioid receptors, these compounds often led to unwanted hallucinations.
However, this latest study identifies a potential breakthrough, offering pain relief without addiction and bypassing the hallucination-causing pathway.
Traditional painkillers such as morphine, oxycodone, and illicit drugs like heroin and fentanyl target mu opioid receptors, providing pain relief while inducing a sense of euphoria that contributes to addiction.
An alternative approach explored by researchers involves the kappa opioid receptor. Drugs that specifically target this receptor effectively alleviate pain, but they can also come with side effects such as hallucinations.
By examining the mechanisms behind hallucinations, scientists at the Center for Clinical Pharmacology at Washington University School of Medicine and the University of Health Sciences & Pharmacy in St. Louis have made a significant breakthrough.
Utilizing electron microscopes, they discovered how a natural compound related to the salvia plant selectively binds to the kappa receptor, triggering hallucinations.
“Since 2002, scientists have been trying to learn how this small molecule causes hallucinations through kappa receptors,” explains principal investigator Tao Che. “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.”
These findings open the door to developing new drugs that target the specific binding sites on the kappa receptor, providing pain relief without the addictive problems associated with traditional opioids and the hallucinations linked to current drugs that selectively target the kappa opioid receptor.
Addressing the opioid epidemic, which caused over 100,000 overdose deaths in the U.S. in 2021, targeting the kappa receptor for pain relief without hallucinations marks a crucial step forward.
“Opioids, especially synthetic opioids such as fentanyl, have contributed to far too many overdose deaths,” Che points out. “There’s no doubt we need safer pain-relieving drugs.”
Led by first author Jianming Han, PhD, a postdoctoral research associate, Che’s team uncovered that a class of signaling proteins called G proteins activate various pathways of the kappa opioid receptor, including the hallucination-inducing pathway. Understanding the differences between these proteins and how they bind to the receptor offers insights into selectively activating the receptor for pain relief without hallucinations.
“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 adds. “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 now, the role of G proteins has been unclear, especially in relation to the protein responsible for activating the pathway associated with 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,” Che adds. “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.”
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