Students at the Stanford University Medical School listen to a lecture on drug addiction during which the lecturer injects a rabbit with a killing overdose of morphine.
In minutes, the rabbit is near death, comatose and unable to breathe. The lecturer injects the rabbit again, this time with a chemical named naloxone. Seconds later, the rabbit leaps to its feet, fully awake, without a sign of its sudden scrape with death.
"That lecture is one of the most popular in the school," says Dr. Avram Goldstein, professor of pharmacology at Stanford and director of the Addiction Research Foundation in Palo Alto, Calif. "Naloxone is really a dramatic lifesaver."
Naloxone is now stocked in the nation's emergency rooms, where in a few years it has saved untold heroin overdose victims. The drug has just been put into use screening people who say they are heroin addicts seeking treatment with methadone. If they are addicted to heroin, they will show heroin withdrawal symptons minutes after an naloxone injection.
"We don't want to put people on methadone who aren't addicted to heroin," says Goldstein, who has pioneered use of naloxone, "because then all you've done is addicted somebody to methadone."
The discovery of naloxone and how it strips morphine and heroin out of the brain illustrate the dramatic advances being made in brain chemistry. Understanding of the brain is growing so fast that neurobiologists believe they are on the verge of devising new and better treatments for a host of brain disorders, including depression and schizophrenia.
Brain researchers also believe they are close to working out ways of weaning addicts from drugs like heroin and developing new drugs that will kill pain without the habit-forming effects of codeine and morphine.
"A nonaddictive opiate would be the ultimate drug," Dr. Solomon H. Snyder, professor of psychiatry and pharmacology at John Hopkins University School of Medicine, said in an interview. "There is already evidence that chemists are finding opiates that are almost addiction-free."
The discovery of the newest opiate was announced last month by Goldstein, who named the chemical, dynorphin, which is Greek for power. Goldstein found dynorphin in an extract of the posterior portion of the pig's pituitary gland, alongside the animal's brain.How powerful is dynorphin? Goldstein believes it is the most potent pain-killer ever found.
"We think it may be 200 times as powerful as morphine," Goldstein said. "When nature makes something this potent, that means it's important."
Goldstein believes that dynorphin occurs naturally in the brains of a host of mammals, including humans, to h elp them endure and ward off pain. If something as powerful as dynorphin occurs naturally in the brain, why are we not addicted to it? Why do people become addicted to drugs like morphine and heroin that are nowhere near as strong as dynorphin?
"It's likely that something like dynorphin is involved in drug addiction," Goldstein said. "It may be that there is a shortage of dynorphin in an addict's brain. It is not going to be easy, but what we would like to do is measure the dynorphin levels in addicts' brains."
Dynorphiin is one of the chemicals in the brain that scientists call neurotransmitters, meaning they carry information from one brain cell to the next. A few years ago scientists had identified only six such chemicals. Now they have identified 20, of which dynorphin is the latest. Doctors suspect there may be at least 100 and as many as 200, each different and each doing a different job inside the brain.
"Finding these neurocheicals is very analogous to the situation in astronomy," Johns Hopkins' Snyder says, "when people are looking and discovering new kinds of stars all the time."
Finding the chemicals that carry information through the brain hasn't been easy. There's no way to study the chemistry of a live brain, animal or human. So weak was our understanding of how the brain worked that scientists thought information was transmitted through the brain by electrical signals until less than 30 years ago.
The complexity of the brain blocked almost every attempt to understand its chemistry until the 1960s. Though the human brain weighs but three pounds, it is the most intricate three pounds found on Earth. There are more than 50 billion individual nerve cells in the brain, each one having as many as 1,000 possible connections with more than 1,000 other brain cells.
"A single human brain," the National Academy of Sciences wrote last month, "has a greater number of possible connectiions among its nerve cells than the total number of atomic particles in the universe."
Dynorphin is similar to a chemical named beta-endorphin that was found in the brain four years ago by scientists at the Salk Institute in La Jolla, Calif. Just after the discovery of endorphin, scientists in Sweden, Scotland and Johns Hopkins in the United States found two similar chemicals called enkephalins, Greek for "something in the head."
An obscure part of a class of chemical called peptides, the enkephalins were found in brain cells whose nerve endings were next to brain cells found to be receivers of drugs. These receivers were called "opiate receptors" by Hopkins' Snyder, who was first to identify them in 1973.
Snyder found morphine and heroin bind themselves to specific parts of the brain in such an uncanny way that it explained how pain-killers act.
Swarms of opiate receptors were found by Snyder in the region of the brain where pain is perceived. He found them in the brain's limbic system, where euphoria is felt. Opiate receptors flooded the brain cells that regulate breathing and a small area of the brain stem that controls the opening and closing of the eye.
"When you overdose on an opiate, you die because you stop breathing." your eyes constrict. That's how the police detect heroin addicts, looking into their eyes."
Why did morphine and heroin attach themselves to specific brain cells? Doctors knew the brain could not be making these drugs, since humans are not addicted to chemicals in their natural makeup. They reasoned that the brain may make something that is like morphine but is nonaddictive. If this were so, the opiate receptors in the brain could be mistaking drugs like heroin and morphine for whatever nonaddictive pain-killers the brain was making.
This is how doctors discovered the enkephalins. They tested extract of brain parts on pieces of human intestine, which has long been known to shrink when treated with morphine. The enkephalins in the brain extract produced the same effect, shrinking human intestine in just as dramatic a fashion as morphine did.
Doctors soon discovered that the enkephalins could not be used as pain-killers. Being peptides (small proteins), injected enkephalins were rapidly destroyed by enzymes in the body before they reached the brain. The eukephalins also had trouble breaking the body's natural bloodbrain barrier, which protects the brain from harmful substances.
Researchers have rearranged the enkephalin molecule in thousands of ways in an attempt to get around these obstacles. Results so far have been disappointing. Of an estimated 3,000 enkephalin derivatives tested on animals the last two years, only one has made it to testing on humans.
Hopkins' Snyder says researchers now figure enkephalin is destroyed in the brain and are trying to figure out how. He says there must be a mechanism in the brain that disposes of old enkephalin so that fresh chmeical can take its place or the opiate recepter can be left alone to rest.
Dr. Charles Gorenstein at Johns Jopkins has identified three enzymes which appear to break down enkephalin in the body. He says one of the three looks so selective that its major function in the body might be to strip the brain of enkephalin when it is no longer needed to lessen pain.
Finding the enzyme that breaks down enkephaline might turn up a chemical that blocks the enzyme. Combining such a chemical with injected enkephalin could provide a means of getting the pain-killer to the brain before it is destroyed by the enzyme. Stanford's Goldstein is taking the same approach with dynorphin, which has the same trouble getting past the body's enzymes.
Brain researchers now believe enkephalins might be the key to the Oriental practice of acupuncture, the insertion of thin needles into the head to relieve pain. If acupuncture acted by releasing enkephalins, then its effects should be blocked by chemicals like naloxone.
Dr. David Mayer at the Medical College of Virginia applied electrical stimulation to the teeth of volunteers to produce pain, then relieved the pain with acupuncture. Following that, Mayer injected naloxone into the same volunteers and found their pain was no longer relieved. This strongly suggested that at least one form of acupuncture works by triggering the release of enkephalin.
Brain researchers are working on more neurotransmitters than just the enekphalins. One getting a growing amount of attention is dopamine, a neurotransmitter identified 10 years ago in a section of the brain called the striatum which helps control body movement.
Dopamine is produced by dark-strained nerve cells called substantia-nigra , which project their nerve endings directly into the striatum. Doctors had known for more than 50 years that these cells were curiously absent in patients who had died from advanced Parkinson's disease but had never been able to isolate and identify the dopamine generated by these cells.
Soon after the discovery of dopamine, doctors began injecting Parkinson patients with it. Nothing happened. The dopamine never made it past the blood-brain barrier. Neurochemists then worked out the pathway dopamine takes through the brain and discovered it was being formed from another substance called L-dopa, which did cross the bloodbrain barrier.
L-dopa's effect on Parkinsonism is one of the most dramatic advances in recent medical history. Just a few injections of L-dopa eliminate almost all the symptons of this dread disease. The trembling the shaking, the inability to move about stop after treatment with L-dopa.
"It is so successful," says Dr. Richard Thompson of the University of California at Irvine, "that if you matched L-dopa against the insulin treatment for diabetes, it would win hands down."
Ten years of research with dopamine have convinced doctors that it will affect more than Parkinsonism -- for example; at least two symptoms of aging, sinility and the growing inability to move with speed. Injections of L-dopa into aging rats produce a dramatic turnaround in their ability to move. They become more alert. Old rats barely able to swim suddenly rip through the water after L-dopa injections.
"I'm not saying it's a cure for senility," said Thompson, "But there's little doubt that it's a way in rats to reverse one of the problems of aging."
Doctor like Thompson and Snyder believe dopamine may be the clue to the treatment of schizophrenia and severe depression, the two leading causes of mental illness in the United States.
Doctors know that Parkinson patients develop some symtoms of schizophrenia, such as hallucinations and delusions. Even Parkinson patients responding to treatment from L-dopa develop schizoid tendencies after five years of taking L-dopa, in part because it alters the dopamine system in the brain in some poorly understood way.
Moderate doses of L-dopa worsen schizoid symptoms in patients. At the same time, a few anti-schizophrenic drugs recently put on the market work by blocking the receptors for dopamine in the brain.
"The most popular hypothesis of the ultimate cause of schizophrenia," Thompson says, "is some abnormality of the dopamine system in the brain The trouble is, we don't know what that abnormality is."
Depression may also be caused by dopamine imbalance, though it is less clear how that might come about. The most successful treatment of depression involves use of drugs that trigger release of norepinephrine, a neurotransmitter of a class of chemical called the catecholamines. Only two are known so far to exist iin the brain. One is dopamine.
Researchers think the future has never been brighter for treatment of mental disorders. The clues to such treatment are in the neurotransmitters, those already found and those still to be found.
Two suspected neutrotransmitters are insulin and glucagon, peptides like the enkephalins and chemicals that perform opposite functions outside the brain. Insulin lowers blood sugar, glucagon raises blood sugar.
"All the major drugs of psychiatry so far are based on detailed studies of dopamine and norepinephrine," Hopkins' Synder says, "There's no reason to believe they're any more important than the peptide neurotransmitters, which people have just begun to study."