By David N. Leff

Marathon runners will tell you that after running a certain number of the 26.4 miles in the footrace, they feel very exhausted, but press on.

Molecular geneticist Lei Yu, of the University of Cincinnati (Ohio) College of Medicine, puts it this way: "People who do regular running experience this second-wind effect. They feel they are hitting a wall; they can't push themselves further. But if they persist — keep running — after a while they will feel what's called an "endorphin high" — a very nice sensation, as if the fatigue is gone; as if they can run on forever."

Whence this blissful new spurt of energy?

"Sports medicine studies," Yu continued, "show that these runners release a lot of stress-induced endorphins. They think these molecules in the brain perform a mild effect, like heroin or morphine, giving people a moderate euphoric feeling — an endorphin 'high' — to alleviate the physical stress."

Endorphin, often described as 'the brain's own morphine,' is released by the brain's opioid system to perform two physiological functions: one, relieve pain; two, fulfill the craving of narcotic addicts. Moreover, Yu went on, "the opioid system regulates the host defenses against infection and some of the brain's reward pathways, including food and sex.

"Morphine," he told BioWorld Today, "the active ingredient of heroin, is the major component in the opioids. Its original use, centuries ago, was to relieve pain. It was named after Morphia, the Greek god of dreams, and it acts through the mu receptor, so-called because mu is the first Greek letter of Morphia. And that receptor is the biological gateway of morphine's effects in the body."

Yu is one of two senior authors on a paper in today's Proceedings of the National Academy of Sciences (PNAS), dated Aug. 4, 1998. Its title is, "Single-nucleotide polymorphism in the human mu opioid receptor gene alters beta-endorphin binding and activity: Possible implications for opiate addiction."

"When we started this experiment," Yu recounted, "we knew in general that people differ in their biological activity. For example, some may be more sensitive to temperature; others to emotional disturbances. Some people abuse heroin, which is an opioid that causes a socioeconomic problem; others do not."

Comparing Addicts On Methadone With 'Normals'

To compare these two populations and seek the genetic roots of their individual differences, Yu and his co-authors drew on two disparate groups of people:

"One cohort," he recalled, "consisted of 113 men and women who are dependent on opioids. These are former heroin addicts, who take methadone to replace their heroin."

They were recruited by the paper's co-senior author, neuroscientist and clinician Mary Jeanne Kreek, from her methadone clinic. Kreek is head of the neuroscience laboratory at the Rockefeller University in New York City.

"Some of these methadone patients function very normally," Yu observed. "They're good taxpaying citizens. Many are successful professionals — lawyers, physicians — in New York City. The only difference between them and the control cohort is that this group used to abuse heroin and now they are stable on methadone with a normal lifestyle.

"That control cohort," he went on, "was a general population of 39 people like you or me, generally known as normal individuals, without a history of narcotic or alcohol abuse.

"Because we had the normal group as the control," Yu pointed out, "we wanted to see if in the normal, general population, there might be genetic variants for the morphine or mu opioid receptor.

"Drug-seeking behavior," he went on, "is a complex socioeconomic and biological behavior of people who may be predisposed to abuse drugs, but, due to educational and personal circumstances, have never come in contact with such drugs, so that predisposition will never show up.

"In other words," he summed up, "we were thinking that people through some unfortunate experience began using drugs and may be genetically predisposed to addictive behavior. That's why we compared these two groups."

By DNA analysis, the co-authors identified five different single-nucleotide polymorphisms (SNPs) — genomic variants — in the coding region of the mu opioid receptor gene. Of these, the most abundant was at position 118, so they named it A118G.

"It's fascinating," Yu said. "In most people at this position it's A, but in 20 percent of the cohorts we studied, one of their genes is the G variant. Our most important finding," he added, "was that the genetic allele variant actually has a biological function in affecting our own body-made endorphin."

Of the total 152 individuals they studied, the most numerous ethnic contingent was Hispanic, followed by Caucasians and African-Americans. "Early data with this relatively small statistical sample," Kreek told BioWorld Today, "suggest that the A118G percentage among the Hispanic subjects may play a protective role."

Or as Yu put it, "In Hispanics, our data show that this particular variant actually may help people to not get hooked on heroin." He cautioned, however, "We don't have outright proof. Our data show statistically that people who don't use heroin have a much higher probability in Hispanics of hiding this genetic variant.

"What might be a very interesting angle for a bioaudience," Yu offered, "is that such finer, small genetic variability among individuals may be in the future a way of providing differential drug effects against addiction, because one can imagine that the 20 percent of individuals with this particular genetic variant will respond to beta endorphin. So possibly mimetics — drugs that mimic beta endorphin's effects — would make for different therapeutic effects."

He foresees that "in the not too long future, physicians in hospitals or drug clinics would have the ability to detect SNP allelic variability. It should be a relatively simple test, because it's a single-base change."

Kreek also anticipates that further experiments, now in the planning stage, may eventuate at some future time in addiction treatments, "including gene therapy." *