Keys to Body’s Pain Control System Found

In a discovery that promises major progress toward development of new painkillers and treatments for drug addiction, researchers have isolated two key components of the body’s pain control system.

In separate papers published today in the journal Science, researchers at UCLA report the discovery of the long-sought opiate receptor in the brain, while researchers at the Hebrew University of Jerusalem say they have found the natural brain molecule that binds to the marijuana receptor.

With these new elements in hand, researchers should now be able to separate the pain-killing and addictive qualities of opiates such as morphine and heroin to produce painkillers that do not become habit-forming.

Discovery of the marijuana receptor could make it possible to develop drugs that stimulate appetite, control nausea, reduce blood pressure or lower eye pressure in glaucoma without the patient becoming high.

“Both of these findings are really important,” said molecular biologist Michael Brownstein of the National Institute of Mental Health. “They will lead to some very interesting science in the next decade.”

Unlike cocaine and its more lethal formulation, crack, which disrupt brain activity, heroin and marijuana bind to specific proteins--called receptors--on the surface of certain brain cells, much like the way a key fits into a lock. This binding triggers activity within the brain cell.

The recognition more than two decades ago that these drugs bind so specifically to cells led to the conclusion that the body must produce its own chemicals that bind and produce similar effects. An intensive search began to find the receptors and the naturally occurring chemicals that bind to them.

The first success occurred 15 years ago when Solomon Snyder, a neuroscientist at Johns Hopkins University in Baltimore, discovered the endorphins, a family of peptides that bind to the opiate receptors and provide pain relief and a “natural high.”

Then progress slowed. It was only two years ago that a team at the National Institute of Mental Health identified the marijuana receptor in the brain.

Today’s discovery of the opiate receptor and the marijuana-like compounds close the circle, providing researchers with both halves of each system.

The opiate receptor, discovered in the laboratories of Christopher J. Evans, a psychiatrist at UCLA, and Robert H. Edwards, a UCLA neurologist, is called the delta opiate receptor, one of three forms that are known to exist. Now that the delta receptor is in hand, Evans said, researchers should quickly be able to find the mu and kappa receptors--and perhaps others whose existence is only speculative.

Coincidentally, a team headed by biochemist Brigette Kieffer of the Ecole Superiore de Biotechnologie in Strasbourg, France, reported this week in the Proceedings of the National Academy of Sciences that they had also found the delta receptor. Scientists familiar with the work of both groups say they have almost certainly discovered the same protein.

The fact that there are several different receptors for opiates is very encouraging, researchers said. It suggests that each receptor may be responsible for a different aspect of the opiate’s effect on the brain--one for pain relief, one for addiction and so forth. If so, researchers should be able to design drugs to hone in on the receptor that provides pain relief without affecting the receptor that produces addiction.

“The long search for new painkillers that will not produce drug dependence and withdrawal can now be logically pursued,” said Dr. Floyd E. Bloom, a neuropharmacologist at the Scripps Research Institute in La Jolla.

Meanwhile, biochemists William Devane, now at the National Institute of Mental Health in Bethesda, Md., and Raphael Mechoulam of Hebrew University have identified a naturally occurring molecule, much simpler than the primary ingredient of marijuana, that binds to the marijuana receptor. They call the chemical anandamide, from a Sanskrit word meaning internal bliss.

They may have found only one of many such chemicals, however. Two other groups, one at St. Louis University and one at the Bowman Gray School of Medicine in North Carolina, are reportedly close to identifying other compounds that bind to the receptor that are chemically quite different from anandamide.

The fact that several chemicals bind to the receptor is also encouraging, again because they might make it possible to separate the medicinal effects of marijuana analogs from their psychoactive effects.

But before researchers get too far in such efforts, they will attempt to answer a potentially more significant question: What role do anandamide and its ilk, along with the marijuana receptor, play in the complex natural functioning of the brain?

That may produce many surprises, said biologist William Martin of Virginia Commonwealth University. “We will be learning about an entirely new neurochemical system.”