Stronger Medicine Than Morphine?

Scientists have discovered two compounds in the mammalian brain that appear to be members of a long-sought class of natural painkillers. The proteins, described in tomorrow's issue of Nature, could lead to an analgesic that gives more potent pain relief--with fewer side effects--than morphine.

Morphine and similar narcotics dull pain by binding to mu opioid receptors in the brain. For years, scientists have hunted for endogenous chemicals that bind to this receptor, but until now, the only known natural painkillers in the brain were the endorphins, which bind to other receptor types.

Determined to track down the fugitive proteins, neuroscientist James Zadina and his colleagues at the Veterans Affairs Medical Center in New Orleans went fishing. They tinkered with the structure of a peptide known to bind weakly to mu receptors in the test tube until they had created two that latched on tight. Like endorphins, these compounds are short peptides, each just four amino acids long.

Zadina's team tested the compounds' ability to dull pain by injecting them into the brains and spinal cords of mice, then placing each mouse's tail under a hot light. Mice injected with the peptides left their tails in the heat longer than those injected with morphine did. To determine whether these compounds exist naturally in the brain, Zadina's group mixed antibodies to them with ground-up cow brains. The antibodies latched onto the right targets, which were then dubbed endomorphin-1 and endomorphin-2.

"This appears to be a very important finding," says Martin Wessendorf, a neuroanatomist at the University of Minnesota, Minneapolis. But to confirm that endomorphins are the real McCoy--the long-sought mu-receptor proteins--researchers must still pinpoint their exact location in the brain and how they function. "We know that it's in the brain," Wessendorf says, "but we don't know if it's made or released by nerve cells." There's plenty of enthusiasm to test the peptides. "They should provide new molecular tools for dissecting the endogenous opiate pathways in the brain and the spinal cord," says David Julius, a neuropharmacologist at the University of California, San Francisco. For his part, Zadina is ready to develop the next generation of painkillers. Versions of endomorphins, he says, might work without morphine's side effects, such as nausea and addiction.