Why Zebras Don't Get Ulcers: The Acclaimed Guide to Stress, Stress-Related Diseases, and Coping

by Robert M. Sapolsky

Why not just let it remain at the enhanced, improved level achieved in the first thirty minutes and get the benefits of an activated immune system all the time? Metaphorically, why not have your military that defends you always on maximal alert? For one thing, it costs too much.

system that’s always on maximal, hair-trigger alert is more likely to get carried away at some point and shoot one of your own guys in a friendly fire accident. And that’s what can happen with immune systems that are chronically activated—they begin to mistake part of you for being something invasive, and you’ve got yourself an autoimmune disease.

Two facts about autoimmunity: 1. Insofar as autoimmune diseases involve over activation of the immune system (to the point of considering a healthy constituent of your body to actually be something invasive), the most time-honored treatment for such diseases is to put people “on steroids”—to give them massive amounts of glucocorticoids. The logic here is obvious: by dramatically suppressing the immune system it can no longer attack your pancreas or nervous system, or whatever is the inappropriate target of its misplaced zeal (and, as an obvious side effect to this approach, your immune system will also not be very effective at defending you against real pathogens). Thus, administration of large amounts of these stress hormones makes autoimmune diseases less damaging. Moreover, prolonged major stressors decrease the symptoms of autoimmune diseases in lab rats.

At the same time, it appears that stress can worsen autoimmune diseases. Stress is among the most reliable, if not the most reliable, factor to worsen such diseases. This has often been reported anecdotally by patients, and is typically roundly ignored by clinicians who know that stress hormones help reduce autoimmunity, not worsen it.

repeated stress increases the risk of autoimmune disease. As we would now expect, if you instead have massive prolonged stressors, or are administered big hefty doses of glucocorticoids, you put the system in phase C—dramatic immune suppression, which decreases the symptoms of autoimmunity.

some quick rounds of replication. And when are immune systems often at their lousiest? You got it. It’s been endlessly documented that latent viruses like herpes flare up during times of physical or psychological stress in all sorts of species.

when circulating glucose concentrations are elevated in rats during stress, at least one kind of experimental tumor can grab the glucose before the muscle does. Your storehouses of energy, intended for your muscles, are being emptied and inadvertently transferred to the ravenous tumor instead.

there is no particular support for the idea that stress increases the risk of cancer

Is there a cancer-prone personality, and can it be interpreted in the context of coping poorly with stress? Some scientists think so. Much of the work in this area has been done with breast cancer, in part because of the prevalence and seriousness of the disease. However, the same pattern has been reported for other cancers as well. The cancer-prone personality, we’re told, is one of repression—emotions held inside, particularly those of anger. This is a picture of an introverted, respectful individual with a strong desire to please—conforming and compliant.

Most of these studies have been retrospective or quasi-prospective, and we have seen the problems endemic to such studies. Nonetheless, the prospective studies have shown there to be some link, though a small one.

So collectively, we have, with the exception of two studies concerning one type of cancer, no overall suggestion that stress increases the risk of cancer in humans.

What if your cancer has been cured? Does stress increase the risk of it coming back? The handful of studies on this subject don’t suggest that there’s a connection—a few say yes, an equal number, no.

once you have cancer, will stress make a tumor grow faster, increasing your risks of dying from the disease?

When you compare patients who respond to their cancer with a “fighting spirit” (that is, they are optimistic and assertive) with those who collapse into depression, denial, and repression, the former live longer, after controlling for cancer severity.

The landmark study of this type was carried out in the late 1970s by the psychiatrist David Spiegel of Stanford University. Women who had just gotten a metastatic breast cancer diagnosis were randomly assigned to either a group that received standard medical care or a group that, in addition, had intensive supportive group psychotherapy with other breast cancer patients. As Spiegel has emphasized in his accounts of this famous study, he went into it anticipating that the group therapy intervention might decrease psychological distress in patients, but he certainly didn’t expect that it would affect the biology of the cancer. Amid his skepticism, what he found was that the group therapy intervention extended life span an average of eighteen months, a whopping great effect.

In what was probably the most thorough attempt at a replication of Spiegel’s findings, a study published in 2001 in the prestigious New England Journal of Medicine, there was no effect on survival time.

But do cancer patients with more psychosocial support have better immune function (step 3)? Seemingly. Breast cancer patients who reported more stress had lower activities of those natural killer cells, while there’s higher NK cell activity in women who report more social support or who received some sort of group therapy intervention.

There seems to be a link between a certain personality type and a somewhat greater cancer risk, but no studies have shown where stress physiology fits into that story, nor have lifestyle confounds been ruled out.

Everything bad in human health now is not caused by stress, nor is it in our power to cure ourselves of all our worst medical nightmares merely by reducing stress and thinking healthy thoughts full of courage and spirit and love. Would that it were so. And shame on those who would profit from selling this view.

Pain is useful to the extent that it motivates us to modify our behaviors in order to reduce whatever insult is causing the pain, because invariably that insult is damaging our tissues.

The strength of a pain signal, for example, can depend on what other sensory information is funneled to the spine at the same time. This, it turns out, is why it feels great to have a massage when you have sore muscles. Chronic, throbbing pain can be inhibited by certain types of sharp, brief sensory stimulation.

fibers carrying pain information from your periphery to the spinal cord—are not all of one kind. Instead, they come in different classes. Probably the most relevant dichotomy is between fibers that carry information about acute, sharp, sudden pain and those that carry information about slow, diffuse, constant, throbbing pain. Both project to spinal cord neurons and activate them, but in different ways

As things are wired up, when a sharp, painful stimulus is felt, the information is sent on the fast fiber.

By contrast, when a dull, throbbing pain is felt, the information is sent on the slow fiber.

The pain physiologist David Yeomans has framed the functions of the fast and slow fibers in a way that fits perfectly with this book: what the fast fibers are about is getting you to move as quickly as possible (from the source of the piercing pain). What the slow fibers are about is getting you to hunker down, immobile, so you can heal.

But sometimes, something goes wrong with pain pathways somewhere between those pain receptors and your spine, and you feel pain long after the noxious stimulus has stopped or the injury has healed, or you feel pain in response to stimuli that shouldn’t be painful at all. Now you’ve got problems—allodynia, which is feeling pain in response to a normal stimulus.

We started with pain receptors scattered all over the body, and have gotten as far as the spinal cord receiving projections from them. From there, a lot of those spinal neurons that are activated by pain send projections up into the brain.

The brain’s interpretation of pain can be extremely subjective.

But most of what the brain’s responses to pain are about is generating emotional responses and giving contextual interpretations about the pain.

how much pain you feel, and how unpleasant that pain feels, can be two separate things.

emotive parts of the brain not only can alter how you respond to pain information coming up the spinal cord; those areas of the brain can alter how the spinal cord responds to pain information.

This can be shown in animals with the “hot-plate test,” Put a rat on a hot plate; then turn it on. Carefully time how long it takes for the rat to feel the first smidgen of discomfort, when it picks up its foot for the first time (at which point the rat is removed from the hot plate). Now do the same thing to a rat that has been stressed—forced to swim in a tank of water, exposed to the smell of a cat, whatever. It will take longer for this rat to notice the heat of the plate: stress-induced analgesia.

the opioids were synthesized and released in parts of the brain that regulated pain perception, and they would make some of the neurons that relay pain signals in the spine less excitable. (Opiate refers to analgesics not normally made by the body, such as heroin or morphine. Opioid refers to those made by the body itself.

Acupuncture stimulates the release of large quantities of endogenous opioids, for reasons no one really understands. The best demonstration of this is what is called a subtraction experiment: block the activity of endogenous opioids by using a drug that blocks the opiate receptor (most commonly a drug called naloxone). When such a receptor is blocked, acupuncture no longer effectively dulls the perception of pain.

knowing that a pain-reducing procedure is being carried out adds to its effectiveness.

stress releases opioids as well.

stress triggers the release of one type of endorphin, beta-endorphin, from the pituitary gland.

stressors produce similar effects. Surgery, low blood sugar, exposure to cold, examinations, spinal taps, childbirth—all do it.

So stress blocks pain perception, enabling you to sprint away from the lion despite your mauling, or at least to put up with the muscle ache of smiling obsequiously non-stop during the stressful meeting with the boss. This explains everything. Unless it happens to be the sort of stressful situation that makes pain worse instead of better.

but what if you’re the sort of person where just seeing the nurse taking the cap off the hypodermic needle for the blood draw makes your arm throb? What we’ve got now is stress-induced hyperalgesia.

it involves more emotional reactivity to pain, interpreting the same sensation as more unpleasant. So stress-induced hyperalgesia is just in your head. On the other hand, so is stress-induced analgesia, just a different part of your head. The pain-ometer parts of your brain respond to pain normally in people with stress-induced hyperalgesia. It’s the more emotional parts of the brain that are hyperreactive, the parts of the brain that are the core of our anxieties and fears.

Just like, “Stress can increase appetite. And it can decrease it, too,” we’ve got, “Stress can blunt pain perception. But sometimes it does the opposite.”

analgesia arises more in circumstances of massive, physical injury. Half your body is burned and your ankle’s sprained, and you’re trying to carry a loved one out of some inferno—that’s when stress-induced analgesia is going to dominate. Discover some weirdo growth on your shoulder that hurts a bit, decide in a panic that you’ve got fatal melanoma, be informed by an unsympathetic answering machine that your doctor has just left for a three-day weekend. That’s when the stress-induced hyperalgesia will dominate, as you lie awake for three nights, thanks to how painful you’ve now decided the spot feels.

Fibromyalgia. This is the mysterious syndrome of people having markedly reduced pain tolerance and multiple tender spots throughout the body, often paralyzing extents of pain, and no one can find anything wrong—no pinched nerve, no arthritis, no inflammation.

fibromyalgia is more likely to strike people with anxious or neurotic personalities.

sufferers have abnormally high levels of activity in parts of the brain that mediate the emotional/contextual assessments of pain, the same areas activated in stress-induced hyperalgesia. Moreover, their cerebral spinal fluid contains elevated levels of a neurotransmitter that mediates pain (called Substance P). And, as noted in chapter 2, unexpectedly, glucocorticoid levels are below normal in people with fibromyalgia.

What happens with pain perception when there is chronic stress? With stress-induced hyperalgesia, the answer seems to be, the pain just keeps going, maybe even worsens. But what about stress-induced analgesia? In the acute, lion-mauling scenario, it is adaptive.

Stress-induced analgesia does not go on forever, and the best evidence ascribes this to depletion of opioids. You are not permanently out of business, but it takes a while for supply to catch up with demand.

the soothing effects of stress-induced analgesia are just a short-term fix. And for the elderly woman agonizing through terminal cancer, the soldier badly injured in combat, the zebra ripped to shreds but still alive, the consequence is obvious. The pain will soon return.

And then there’s those mysterious penile or clitoral erections that occur intermittently during the night.