Researchers identify potential safe route to pain relief

Strategies to treat pain without causing dangerous side effects such as euphoria or addiction have proven elusive. We have attempted to develop drugs that selectively activate certain types of opioid receptors to treat pain without activating other opioid receptors. Unfortunately, these compounds can cause another unwanted effect: hallucinations. However, new research led by the Washington University School of Medicine in St. Louis has identified potential pain-reducing pathways that do not cause addiction or activate hallucinogenic pathways.

The study will be published in the journal May 3 Nature.

Analgesics such as morphine and oxycodone, and illicit street drugs such as heroin and fentanyl, activate what are known as mu-opioid receptors in neurons. Those receptors relieve pain, but they also cause euphoria -; feeling high. And that feeling leads to addiction. Another strategy is to target another opioid receptor called the kappa opioid receptor. Scientists trying to create drugs that target only the kappa receptor have also found that they effectively relieve pain, but may be associated with other side effects such as hallucinations.

Researchers at the University of Washington School of Medicine’s Center for Clinical Pharmacology and the University of Health Sciences and Pharmacy, also in St. Louis, are trying to understand the potential mechanisms behind such hallucinations, with the goal of developing this pain reliever without side effects. identified. They used electron microscopy to identify how a natural compound associated with the salvia plant selectively binds only to kappa receptors, causing hallucinations.

Since 2002, scientists have been trying to understand how this small molecule triggers 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 do not cause hallucinations.”

Tao Che, PhD, Principal Investigator, Assistant Professor of Anesthesiology

Developing new drugs that target these other kappa receptor binding sites would eliminate the addictive problems associated with older opioids and the hallucinations associated with existing drugs that selectively target kappa opioid receptors. may provide pain relief.

Targeting the kappa receptor to block pain without hallucinations would be an important step forward, Che said. Because opioid drugs that interact with the mu opioid receptor are causing the current opioid epidemic, he is responsible for over 100,000 overdose deaths in the United States in 2021.

“Opioids, especially synthetic opioids such as fentanyl, contribute to too many overdose deaths.”

Che’s team, led by first author Dr. Jianming Han, a postdoctoral researcher in Che’s lab, found that a class of signaling proteins called G proteins activate the kappa opioid receptor through several different pathways. Did.

“There are seven G proteins associated with the kappa receptor, and they are very similar to each other, but differences between the proteins may help explain why some compounds cause side effects such as hallucinations. “By knowing how each protein binds to a kappa receptor, we hope to find ways to activate that receptor without causing hallucinations.”

The function of G proteins, particularly those that activate pathways leading to hallucinations, has been largely unknown.

“All of these proteins are similar to each other, but the specific protein subtype that binds to the kappa receptor determines which pathway is activated,” Che said. “We found that hallucinogens can preferentially activate certain G proteins, but not other related G proteins. It suggests that it can be isolated: a treatment that kills pain by activating kappa receptors without activating specific pathways that cause hallucinations.