o After being released by the pituitary gland, the stress hormone ACTH can impede production of the body's natural pain relievers, endorphins, leading to a general feeling of discomfort and heightened pain after injury. High levels of ACTH also trigger excess serotonin, now linked to bursts of violent behavior.

By charting the pathways stress hormones take throughout the body, biological cartographers are doing more than mapping the links between stress and disease. Having caught cascades of biochemicals in flagrante delicto, researchers are diagramming the exact lines of communication between mind and body. Ultimately, they will force us to erase the dividing line between what is biological and what is psychological.

Important as they are, elucidating the neurohormones released during stress and relating them to body systems is not even the whole story. If that were all there was to how stress works, you would expect any physical reaction to occur immediately, since these hormones typically remain elevated for only a short time. And you would expect everyone to show some physical reaction. Certainly, not all people suffer a heart attack or asthma attack when they get upset. Some seem able to take stress in their stride, while others routinely are hobbled.

Lawrence Brass, M.D., associate professor of neurology at Yale Medical School, found that severe stress is one of the most potent risk factors for stroke more so than high blood pressure--even 50 years after the initial trauma. Brass studied 556 veterans of World War II and found that the rate of stroke among those who had been prisoners of war was eight times higher than among those veterans who had not been captured.

The findings at first confused Brass. After all, the stress hormones that cause heart disease and stroke are elevated only for a few hours after a stressful event. "I began to realize we would have to take our understanding of stress farther when I began to see that in some people stress can cause disease years after the initial event," he says. He concluded that the immediate effect of the war trauma on the stress response system had to have been permanent. "The stress of being a POW was so severe it changed the way these folks responded to stress in the future--it sensitized them."

Their neurohormonal system was kicked off-kilter. Instead of churning out the normal amount of hormones in the face of stress, their systems were now so deregulated that at the slightest provocation, they either pumped out too much of some chemicals needed or not enough of others. "Years of this kind of hormonal assault may have weakened their cardiovascular systems and led to the strokes," Brass says.

Brass was unable to document actual changes in the neurohormonal system. But another study, of child abuse victims, reported at a meeting of the American Psychiatric Association, provides some of the earliest proof that stress can physically alter people. With magnetic resonance imaging, researchers took pictures of the brains of 38 women, 20 with a documented history of sexual abuse, 18 without. Among those women sexually abused as children, the researchers discovered, the hippocampus is actually smaller than normal. A tiny seahorse-shaped structure in the middle of the brain, the hippocampus is partially responsible for storing short-term memory. It is activated by some of the same neurohormones released during stress. "What we are seeing," says Murray Stein, Ph.D., of the University of California at San Diego, "is evidence that psychological stress can change the brain's makeup."

If stress sensitization begins with a major trauma and results in wholesale neurochemical and neuroanatomical changes, there should be other examples of its ravages. Perhaps, but they won't be easy to find, says UMass's King. "Most kids who suffer a trauma are not brought to the doctor," she says. "They get through the problem, go on with their lives, and wind up in our offices years later, suffering from depression or heart disease. And unless we were able measure amounts of hormones released before the initial exposure to stress, we wouldn't know if the levels were elevated." So researchers are looking at laboratory animals.

Even the lowly rat appears to become sensitized to stress. One study at UMass found that rats repeatedly stressed by exposure to a life-threatening cold and being deprived of maternal contact immediately after birth became hyper responsive to stress. "Rats stressed from birth had a blunted release of ACTH in response to later stress," reports King. Then she reexposed them to cold after the age of 14 days, when their hypothalamic-pituitary axis matures. "Without enough ACTH, the rats were less able to mount a fight-or-flight response. The trauma of the early stress seems to have altered their response system."

"Hormonal changes from stress sensitization are quite clear in animals," notes Delaware's Levine. His own studies of monkeys document permanent changes in cortisol output in response to stress among monkeys subjected to early psychological trauma. "What's interesting are the fine variations in the changes depending on the type and time of the trauma," Levine says.