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A Refrain From Pain In the Brain

July 1, 1997

Judith Zwolak

Tulane researchers have found a natural painkilling chemical in the brain that acts at the same site as the drug morphine. This discovery could eventually lead to new drug addiction treatments and advances in pain medication, says principal investigator James Zadina, adjunct professor of medicine and co-director of the Neuroscience Training Program at Tulane.

Zadina performed this study at the Veterans Affairs Medical Center in New Orleans, where he is director of the Neuroscience Laboratory. Opiate drugs--and their natural counterparts that are produced in the brain--act at three specific sites in brain cells called the delta, kappa and m5 receptors. Like a key fitting into a lock, the opiate binds to a specific receptor and unleashes a myriad of intracellular activity resulting in effects such as euphoria and pain relief.

"For about 20 years, we've known that the body makes things somewhat like morphine," Zadina says. "But none of them were very selective for what we think is the most important receptor--m5, the morphine receptor."

In 1992, Zadina and his colleagues found a peptide, or a short string of amino acids, made in the brain that bound only to the m5 receptor but also found that it didn't elicit a strong response.

"So what we did was to take the structure of that peptide, which was selective but not very strong, and changed it in all of the ways we could think of that the body might modify it," he says.

In the lab, Zadina played a molecular version of pin the tail on the donkey with the four amino acids that made up the peptide. He knew the first three amino acids of the peptide were "about as good as we were going to get in terms of binding." The amino acid in the fourth position was the missing link.

By adding each of the 20 naturally occurring amino acids to the fourth position and then testing for receptor selectivity and binding strength, the researchers hoped to find a potent opiate that the brain could make on its own. They found their substance when they placed the amino acid phenylalanine in the fourth position.

"In terms of potency and selectivity, both measures were off the scale," he says. "This peptide had an affinity 50 times greater than the other peptide and didn't bind with any of the other receptors."

The more difficult part of the research, Zadina says, was showing that the body actually made their "test-tube" peptide.

"The brain makes an ocean of peptides," he says. "The strategy was to make an antibody that recognized the peptide and use that to find this needle in the haystack."

Using cow brain extracts, the researchers used the antibody to find the peptide during a complicated purification process. They found that the mammalian brain did in fact make their specific peptide and another very similar one. The peptide also proved to be biologically active--it acted as a pain reliever when tested on mice.

"That's the most important thing that morphine does; it's a painkiller," Zadina says. "This peptide worked beautifully. It is very strong and lasted surprisingly long."

The next step for Zadina's group is to find which part of the brain produces the peptide and under what circumstances. They also will attempt to find the gene responsible for making the substance. "Finding the gene will help us study what kind of manipulations might increase the amount of this peptide," he says. "It might be something like a stressful situation or the result of running very hard."

Human studies concerning this natural opiate are still five or 10 years away, Zadina says. "Down the road, we hope for a couple of possibilities for this discovery," Zadina says. "One would be a new generation of painkillers. We hope we can capitalize on some aspects of this peptide that may not have as many side effects as morphine." This research could also lead to new therapies for drug addiction.

"Working in our favor is the fact that every therapy used today, such as methadone, as well as several in clinical trials, are directed toward the same receptor--the m5 receptor," Zadina says. "This new structure affects some cellular processes differently than what's come before. We have the potential to develop a new drug along these lines."

Pain relief and treatment for drug addiction are the factors driving the Department of Veterans Affairs' funding of this research, Zadina says. "These are major problems for the whole population, but particularly for veterans," he says. The study appeared in the April 3 issue of Nature magazine. Coauthors include Abba Kastin, chief of endocrinology and clinical professor of medicine; Laszlo Hackler, visiting assistant professor of medicine and Lin-Jun Ge, research biochemist and associate professor of medicine.

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