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A compound that works similarly to morphine but without dangerous side effects has shown promise at reducing pain in mice.

Why it matters:

Doctors are wary of administering opioid analgesics to treat pain. For one thing, there is the possibility of addiction. But even in patients without the potential for becoming addicted, an opioid overdose can be deadly because a side effect of opioids is their tendency to slow breathing or stop it altogether. So researchers have been interested in finding painkillers that don’t have this problem.

The nitty gritty:

The receptor that responds to morphine, called μOR, triggers two effects in the presence of the drug: pain relief and suppression of breathing. A team of researchers, including Dr. Brian Kobilka, a Stanford University professor of molecular and cellular physiology, wanted to find a molecule that would do the former but not the latter.


They began by computer-modeling 3 million commercially available chemicals in combination with the μOR receptor. They then narrowed it down to 2,500 molecules with the best fit, and further down to 23 that looked most promising.

Kobilka credits fellow researcher Brian Shoichet, a professor of pharmaceutical chemistry at UCSF, with figuring out that step: “His approach was, if you want to find something that behaves differently, you have to find something that looks different from other drugs. So we focused on compounds that look nothing like the usual opiates,” Kobilka said.


The most promising molecule they found is called PZM21. The researchers say that it has “excellent selectivity for the opioid receptor.” In mice, it produced pain-killing effects in mice comparable to those of morphine, but longer-lasting. More importantly, PZM21 preferentially triggers the pathway responsible for pain relief, while having no effect on the pathway responsible for arrested breathing. The findings were published in Nature.

You’ll want to know:

In a commentary accompanying the report, McGill University researcher Brigitte Kieffer, who was not involved in the research, wrote that the pain relieving effects “supersede the adverse effects classically observed for morphine.” But she also pointed out that it wasn’t clear whether the pain relief would last or for how long. “The authors did not investigate whether animals develop tolerance to PZM21,” she wrote.

What’s next:

Kobilka said he would like to make sure that the newly discovered molecule will behave the same way consistently. So far, they only have limited evidence that the receptors themselves influence which pathway — pain relief or respiratory arrest — the drug will take. “We don’t actually know how to steer it yet,” he said.

And though the compound did not induce signs of addiction-like behavior in the mice, Kobilka said it’s too soon to say whether PZM21 might have addictive qualities in humans.

The bottom line:

It’s still early stages, but this drug and others like it will be useful alternatives for scientists to explore in the hunt for safer pain relief drugs.