Researchers from the Center for Clinical Pharmacology at Washington University School of Medicine say they have identified a new target for addiction-free pain treatment—alternate binding sites on the kappa opioid receptor. According to the WashU investigators, scientists who are developing drugs that only target the kappa receptor to alleviate pain, have found that it neither triggers addiction, nor activates a pathway that causes hallucinations, the usual unwanted side effects of pain treatments.
Many painkillers, including morphine and oxycodone and illegal street drugs such as heroin and fentanyl, activate the mu opioid receptors on nerve cells. Those receptors relieve pain but produce the feeling of being “high” which contributes to addiction. Attempts to develop drugs that aren’t addictive have turned to targeting the kappa receptor to treat the pain, but have found that while these drugs effectively relieve pain, they can also be associated with other side effects such as hallucinations.
The researchers believe they have discovered how to avoid this side effect. Using electron microscopes, the team found that a natural compound related to the salvia plant selectively binds only to the kappa receptors causes the hallucinations.
“Since 2002, scientists have been trying to learn how this small molecule causes hallucinations through kappa receptors,” said principal investigator Tao Che, PhD, an 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 don’t lead to hallucinations.”
The finding suggests that targeting these alternate binding sites in the kappa receptor could relieve pain without triggering hallucinations associated with existing drugs that target this opioid receptor. This development would be an important step for effective pain medication, Che noted, as opioid drugs that target the mu receptor are the root cause of the current opioid addiction epidemic that contributed to more than 100,000 overdose deaths in the U.S. in 2021.
The team found that G protein signaling causes the kappa opioid receptor to activate a number of 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,” said Jianming Han, PhD, a postdoctoral researcher working the Che lab, and first author of the paper, published today Nature. “By learning how each of the proteins binds to the kappa receptor, we expect to find ways to activate that receptor without causing hallucinations.”
The researchers noted that the function of the G proteins had been mostly unclear until now, especially the role of the protein that activates the pathway linked 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 noted. “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.”
