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Norbert R. Myslinski

The feeling of pain is useful in that it calls attention to an injury or malfunction of a body part. There are times, however, when a person suffers from persistent pain, the cause of which may be difficult to identify.

By investigating the nervous system, scientists are beginning to discover how we feel hurt when our body is damaged or fails to function properly.

Editor's Note: This article is the first in a two-part series on pain and examines our current understanding of how we experience pain. The second piece, scheduled for publication in the February 2003 issue, will take a look at various treatments of pain.

        Whatever triumphs still shall hold the mind,
Whatever gift shall yet enrich mankind,
        Ah! Here no hour shall strike through all the years,
        No hour as sweet as when hope, doubt, and fears,
        'Mid deepening stillness, watched one eager brain,
        With Godlike will, decree the Death of Pain.
-S. Weir Mitchell, "The Life and Death of Pain."

e all dream of a painless world: one without the throbbing headache, the piercing toothache, the agony of childbirth, arthritis, or cancer. To say that we dislike pain is an understatement--some regard it as God's greatest curse. In fact, we spend huge amounts of time, money, and energy trying to alleviate pain, confident that our lives would be easier, happier, and more productive without it.
        What if we could banish pain from our lives? Take the case of eight-year-old Bobby Clark. Since birth, he has been insensitive to bodily harm. He has never shouted or cried because something hurt, never reflexively removed his hand from a hot stove or sharp knife. He continues to be fascinated by things that most of us quickly learn to avoid. He lives in a painless world, but he is neither happy nor healthy.
        Bobby's wounded and maimed body betrays this lack of respect for the destructive world. His skin is covered with scars from sharp objects that he could not feel. His arms are bent and deformed from the many times they were broken. His lips are bitten raw. Some of his fingers are shortened, and others are missing because he did not feel enough to pull them away. Bobby has a rare, inherited disorder of the nervous system, present from birth and affecting the entire body. He will suffer from it for the rest of his life.

Functions and forms of pain

ain is one of our body's most important security systems. One critical factor for our survival is the ability to become immediately aware of injury through the experience of pain. Theologian C.S. Lewis called it the "divine megaphone" through which God speaks to us and commands our attention.
        Pain is a teacher, requiring its pupils to learn, remember, and adapt. Its lessons are valuable to us because we possess these abilities. Simple animals, by contrast, do not have a memory and would not benefit from the negative reinforcement of pain. They are protected by the instinct they need to survive. Thus we see that on the evolutionary tree, pain was a rather late development. Although most primitive life-forms could react to stimuli, actual suffering was not manifested until the limbic system--the emotional part of the brain--was developed, particularly with the advent of mammals.
        Most of us are familiar with the pain associated with cuts, burns, stings, and various other injuries. Once the body heals, the feeling of hurt goes away. Such cases are placed in the category of acute pain.

A mosquito bite activates special injury-sensitive receptors, called nociceptors, in the skin. These receptors, located on certain nerve endings, initiate signals that are transmitted to the brain.

On the other hand, many suffer from ongoing conditions such as back pain, recurrent headaches, cancer, or arthritis. Some continue to feel the hurt of an injury long after the wound has healed. Such cases are grouped in the category of chronic pain.
        There are several general distinctions between acute and chronic pain. While acute pain can be easily localized and has a clearly defined cause, chronic pain is hard to localize and its cause is often ill defined. Acute pain is reduced when the cause is taken away, but chronic pain persists even after the cause (if known) is removed. The autonomic response--including heart rate, respiration, and sweating--is heightened by acute pain, but it adapts to regular levels in cases of chronic pain. A person with acute pain may suffer from anxiety, but someone with chronic pain may suffer from depression.
        Surprisingly, pain that is perceived in one part of the body may be caused by a problem or malfunction in another area. For instance, pain in the lower leg may be the result of a slipped disk in the spinal column. This condition, known as projected pain, arises because a sensory nerve (neuron) that extends into the lower leg is irritated by compression in the spinal cord, and the brain interprets the signals it receives as representing damage to the lower leg.
        Some people experience a similar but slightly different condition, known as referred pain. For instance, a person suffering from a heart attack may experience pain along the inside of the left arm. The reason for this phenomenon is not entirely clear, but it is thought that sensory receptors in the heart and left arm may be linked to a common neuron that extends from the spinal cord, and pain signals sent by the heart are interpreted by the brain as pain in the left arm.

Where does it hurt?

n answering the question "where does it hurt?" most people indicate the injured part of the body. Aristotle, however, might have said that pain exists in the heart, while Bertrand Russell would have said that it exists in the mind. Today's neuroscientists point to the brain, while noting that various parts of the nervous system are activated to respond to bodily damage.
        In the early 1970s, the dominant theory about chronic pain was that it originated in the peripheral nervous system--that is, the system of nerves that extends beyond the brain and spinal cord. This view was advocated by Dr. John Bonica, the "father" of the pain clinic movement, and other leaders in the field. Physicians therefore tried to prevent nerve impulses from reaching the brain by cutting peripheral nerves or blocking them with alcohol.
        Challenging that view, Dr. Benjamin Crue Jr. proposed that chronic pain originates in the brain rather than in the periphery. The observation that pain could not always be blocked in the periphery

Different types of hurtful stimuli elicit dissimilar responses. In addition, research shows gender differences in the way people respond to pain.

indicated that it was already in the head. In fact, the cutting of peripheral nerve fibers sometimes increases the pain rather than relieving it. In addition, referred pain, projected pain, and the effectiveness of placebos all point away from the injured part as the source of our pain. The ultimate argument is that amputees still feel pain in their phantom limbs.
        Recently, researchers have discovered that the skin and other tissues contain specific receptors-- called nociceptors--that are sensitive to injury or potential injury. When these receptors (which are macromolecules on the surfaces of certain nerve endings) are activated, they initiate messages that are transmitted to the brain. Almost immediately, the motor neurons reflexively move the person's body away from the source of injury, even before he becomes aware of the pain.
        Several areas of the brain take part in processing the signals received. The reticular activating system (a region that projects from the brain stem to the cerebral cortex) directs attention to the source of injury; the parietal lobes of the cerebral cortex help localize the pain and enable the person to realize its importance; and the limbic system adds the suffering component of pain. The experience is then filed into memory by the temporal and frontal lobes of the cerebral cortex.
        Congenital insensitivity to pain (as in the case of Bobby) can occur in various ways. Usually, there is an absence of neurons that normally mediate pain messages from the skin to the spinal cord. In some cases, the cells and tissues of the patient's nervous system are not detectably different from those of a normal person. In such cases, there may be a problem with the functioning of nociceptors in the skin. In other cases, the problem may lie in the processing of emotions in the brain.
        Recent research has shed new light on pain-specific neurons and their corresponding nociceptors. For instance, David Julius and coworkers at the University of California in San Francisco created a mouse with significant insensitivity to heat-induced pain. They did so by removing the gene for a pain receptor protein called VR1 (vanilloid receptor type 1). The mouse demonstrated no aversion to heat at levels that would normally be painful and no distinct preference between plain water and water laced with capsaicin, the spicy ingredient in hot peppers. Evidence suggests that when nociceptors are repeatedly activated by a stimulus, they become increasingly sensitive, leading to the development of chronic pain. Since these receptors are found only on pain-specific neurons, blocking them could help alleviate pain with minimal side effects. The key here is to block these receptors just enough to prevent or turn off chronic pain, without interfering with the important protective acute response. The latter response maintains our reflexes that enable us to quickly withdraw from harm's way.
        The blocking of peripheral pain neurons, however, is not likely to block all types of pain. The glial cells of the nervous system also contribute to pain. Until recently, glial cells were regarded as providing only structural and nutritional support. A recent breakthrough, however, shows that they can produce and maintain chronic pain. According to Linda Watkins of the University of Colorado, spinal cord glial cells release chemicals (called proinflammatory cytokines) that promote pain caused by nerve damage, such as neuralgia, or diseases such as AIDS. All current pain medications alter the function of neurons. These findings suggest an additional area that needs attention in the treatment of pain.

Gender and age issues

ender differences are a relatively new focus for pain research. Until recently, scientists seeking to standardize data used only male animals in most laboratory studies of pain. They thereby eliminated variations induced by cyclic changes in female reproductive hormones and the potential harm to an undetected or future fetus. In addition, many trials of new medications and other treatments excluded women. According to some researchers, it was too costly to include female animals or women in complex studies.
        Then in 1990, the National Institutes of Health (NIH) launched its Office of Research on Women's Health, which drew attention to unmet needs in this area. That was followed by the NIH Revitalization Act of 1993, requiring that women be included in NIH-funded clinical research. In 1996, the NIH established its Pain Research Consortium with representatives from all NIH divisions, and in 1998, this group sponsored the first conference on gender and pain.
        Gender differences include the observation that women report pain more often than men do, in more body regions, and have more severe and persistent pain. Migraine headaches affect mainly women in their childbearing years, decreasing with age. When women and men are given the same pain stimuli in laboratory studies, women say "ouch!" before men do.
        On the other hand, women discriminate better between types of pain and tend to use more coping strategies. The open expression of pain sometimes helps people gain better control over it. Nonetheless, being seen as "too emotional" may work against a person and lead to inadequate care.
        The feeling of pain may also differ with the type of problem. For example, boys rate having braces tightened as more severe than do girls, while girls rate having a broken arm as more painful than do boys. Even so, girls generally grade many procedures as more painful than boys do. In comparable situations, girls are more likely to be fearful and anxious, and boys to be angry.
        Treatment that works for one sex may not work as well (if at all) for the other. For example, narcotic analgesics are less effective in women than in men. Research indicates that sex hormones, primarily estrogen and progesterone in women and testosterone in men, contribute to this variability in pain responses. Pain issues take on greater importance as people grow older. On average, women live six years longer than men. In a recent report on managing chronic pain in the elderly, the American Geriatrics Society estimated that 25--50 percent of those living in society at large have pain problems. About one-fifth of the elderly population reported taking pain-relieving medications several times a week. In nursing homes, however, as many as 80 percent of residents may have substantial pain that is undertreated.
        From an overall perspective, scientists have made great progress in piecing together the increasingly complex puzzle of pain. Nonetheless, much more work remains to be done. Fortunately, the number of new breakthroughs has helped brighten the financial outlook for research in this area. In particular, NIH funding has increased from $67.3 million in 1995 to $157.1 million in 2002. Yet, even as we benefit from current and future discoveries about how to alleviate pain, we can think about Bobby--the child with congenital insensitivity to pain--and consider that under many circumstances, pain can be a blessing rather than a curse.

On the Internet
American Pain Society
Chronic Pain: Hope Through Research
International Association for the Study of Pain
Pain--Hope Through Research

Norbert R. Myslinski is associate professor of neuroscience at the University of Maryland. He is also director of the International Brain Bee and Maryland Brain Awareness Week.

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