Opioid receptor analysis reveals way to treat pain without causing euphoria or hallucinations

By Nick Paul Taylor, The Science Advisory Board contributing writer

May 3, 2023 -- The analysis of an opioid receptor has revealed a potential way to treat pain without causing addiction or hallucinations, two key barriers to the safe use of painkillers today.

The addictive properties of painkillers such as morphine and oxycodone, as well as illegal street drugs such as heroin, stem from their targeting of mu opioid receptors on nerve cells. Engaging the receptors relieves pain but also causes euphoria, the "high" feeling that contributes to addiction. The need to find a way to treat pain without causing addiction has led scientists to study other opioid receptors.

Kappa opioid receptor is a potential alternative target but, while engaging it can inhibit pain signals, it also has features that complicate its use in the treatment of pain. Some researchers have reported that targeting the receptor causes a sense of unease or dissatisfaction, while Salvinorin A, a natural product related to the salvia plant that binds to the target, has hallucinogenic properties. The findings have spurred research into how to achieve the painkilling properties without causing the undesirable effects.

A study published in Nature on Wednesday advances the attempt to untangle the effects of targeting the kappa opioid receptor. Led by scientists at Washington University School of Medicine in St. Louis, a team of researchers used electron microscopes to show how a salvia plant compound binds to the target.

The analysis showed that a class of signaling proteins, the G proteins, cause the kappa opioid receptor to activate several pathways. In a statement, Jianming Han, PhD, a postdoctoral research associate at Washington University, explained how the findings could support the development of drugs that treat pain without causing 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 said. "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 G proteins are similar to each other, but the specific protein subtypes that bind to the kappa receptor dictate which pathways will be activated. Hallucinogenic molecules preferentially activate one specific G protein but not other related proteins. A drug that targets kappa receptor binding sites in a specific way could trigger the painkilling pathways without activating the hallucinogenic G protein.

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