Once people realized that opioid drugs could cause addiction and deadly overdoses, they tried to use newer forms of opioids to treat the addiction to its parent. Morphine, about 10 times the strength of opium, was used to curb opium cravings in the early 19th century. Codeine, too, was touted as a nonaddictive drug for pain relief, as was heroin.

Those attempts were doomed to failure because all opioid drugs interact with the brain in the same way. They dock to a specific neural receptor, the mu-opioid receptor, which controls the effects of pleasure, pain relief and need.

Now scientists are trying to create opioid painkillers that give relief from pain without triggering the euphoria, dependence and life-threatening respiratory suppression that causes deadly overdoses.

That wasn't thought possible until 2000, when a scientist named Laura Bohn found out something about a protein called beta-arrestin, which sticks to the opioid receptor when something like morphine activates it. When she gave morphine to mice that couldn't make beta-arrestin, they were still numb to pain, but a lot of the negative side effects of the drug were missing. They didn't build tolerance to the drug. At certain dosages, they had less withdrawal. Their breathing was more regular, and they weren't as constipated as normal mice on morphine.

Before that experiment, scientists thought the mu-opioid receptor was a simple switch that flicked all the effects of opioids on or off together. Now it seems they could be untied. "The hope is you'd have another molecule that looks like morphine and binds to the same receptor, but the way it turns the receptor on is slightly different," says Dr. Aashish Manglik, a researcher at Stanford University School of Medicine who studies opioid receptors.

After Bohn's discovery, a number of people, including a team that includes Manglik, started looking for a drug that could connect to the mu-opioid receptor in a way that avoids the negative effects of beta-arrestin.

To do that, they mapped the receptor's structure in a computer program and started looking for chemicals that would stick to it. "We tried to look for molecules that would still bind to this 3-D structure, but are as far away from morphine and codeine as possible," Manglik says.

The team ran 3 million possibilities through the computer and picked the 23 best candidates to test in a lab. One chemical, PZM21, seems to do what they hoped: Turn the opioid receptor on without using much beta-arrestin. They report their findings in Nature on Wednesday.

The scientists then tweaked the chemical to make it more potent and gave it to mice. The mice had pain reduction similar to that with morphine. But their breathing was more normal, and they didn't seem to get high.

"If you give a mouse a drug that activates its reward pathways like cocaine, amphetamine or morphine, the mice just run around more. In this compound, we saw very little of that," Manglik says. The mice also didn't seem to have a preference between the chemical and salt water.

That means it's possible that the compound is less lethal and has less potential for abuse compared to something like morphine, but it still might be as effective of a painkiller. If, of course, it turns out to work in humans. So far it's only been tested in mice.

And the role that beta-arrestin plays in opioids is just one hypothesis. It would be eerily convenient if only the negative effects of opiates are tied to this one protein. The mice that didn't have any beta-arrestin actually seemed to have a stronger preference for morphine over saline. So there may be other things going on that science hasn't teased out yet.

But the work that Manglik and his collaborators have done is encouraging in the search for the next generation of painkillers — ideally ones that are safer and non-addictive.

"I think this was really a tour de force," says Gavril Pasternak, a researcher at the Memorial Sloan Kettering Cancer Center who's also trying to develop new opioids but was not involved in this study. "They're new entities with totally different pharmacological profiles. These are great promise for opiates over the course of the next five to 10 years."

Bohn, now a professor at The Scripps Research Institute in Jupiter, Fla., is hopeful that a safer opioid may be coming to the clinic, too.

Manglik and some of his collaborators have founded a company that will try to bring these new drugs to market, and the pharmaceutical company Trevena is running a very similar molecule through clinical trials now.

But that safe, effective painkiller isn't here yet, Bohn says. "We have some really gorgeous compounds, and I think opiates are a terrible epidemic. But I would be careful of overselling this as the answer."

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