The prospect of a non-addictive alternatives to morphine and other opioids has moved a step closer as scientists say they have cracked a key challenge in developing safe and effective substitute painkillers.

Overuse of highly addictive opioids has led to a health crisis across the world, especially in the US where more than 60,000 people died after overdoses in 2016 alone; president Donald Trump has declared the epidemic a public health emergency.

Researchers looking for alternatives examined a receptor protein that interacts with opioids in the brain, and have now revealed its structure as it binds to a molecule related to morphine. While the structure of the receptor had previously been reported, this is the first time scientists have unveiled its structure as it interacts with a drug.

The development, they say, could prove pivotal. The protein, known as the kappa opioid receptor, is one of four that interacts with opioids, but – crucially – while it can trigger pain-killing effects, it is not linked to problems including constipation, addiction risk and death as a result of overdose.

“Tens of thousands of people are dying every year in the US because of opioid overdoses; in the last year more than 50,000 people died. That is as many as died in the Vietnam war in the US. It is a terrible, terrible crisis,” said Bryan Roth, co-author of the research from the University of North Carolina at Chapel Hill.

An illustration of the kappa opioid receptor bound to a morphine derivative (purple). Illustration: Tao Che and Daniel Wacker/ Roth Lab/UNC School of Medicine

Roth adds that understanding the structure of the kappa opioid receptor, and how it interacts with opioids, could help scientists develop drugs that bind only to that particular protein, resulting in far safer painkillers.



While the kappa opioid receptor can also generate unwanted side effects such as hallucinations or feelings of unease when it interacts with drugs, the team say the latest work, published in the journal Cell, provides crucial information that will help them to design medications that only trigger a pain-relieving effect.

“There is a suggestion that targeting certain parts of the receptor would be more beneficial and others would basically [trigger] hallucinations, dysphoria, that sort of thing,” said Roth.



To test the theory, the team explored the structures of various molecules known to interact with the kappa opioid receptor, as well as looking at how certain molecules interact with receptors whose structure had been tinkered with.



Roth said the findings allowed the team to design and produced a drug that interacted only with kappa opioid receptors – although the team note that it has only been tested in cell cultures so far.



“We basically solved the structure and then we are able to make medications that have the signalling properties that we desired,” said Roth.

However while the development holds promise for drug development, it is unlikely to provide new options in the short term; Roth notes it will be some years before such drugs are available to patients.

