Indiana University Research & Creative Activity


Volume 30 Number 2
Spring 2008

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J Michael Walker
J. Michael Walker

Editor's Note: On January 5, 2008, J. Michael Walker, 57, died at home due to natural causes. At the time of his death, Walker, a professor of psychology and neuroscience, was director of the Linda and Jack Gill Center for Biomolecular Science at Indiana University Bloomington. In November 2007, Walker sat down for an interview with writer Jeremy Shere. The story that follows was completed before Walker's death.

Feeling Our Pain

by Jeremy Shere

According to the American Pain Foundation, more than 75 million American suffer some form of serious pain every year. Of those, nearly 50 million struggle with chronic pain that can last for months and years at a stretch. The National Institutes of Health have estimated that chronic pain costs Americans more than $100 billion a year in medical expenses, lost wages, and lowered productivity. Although pain management is big business, modern medicine has yet to develop a drug or treatment besides morphine that really works.

That's why every year more than 6,000 researchers gather for the World Congress on Pain, including J. Michael Walker, a neuroscientist at IU Bloomington and one of the world's leading experts on the molecular mechanisms of pain. Like his colleagues at the World Congress, Walker asks questions about the essence of pain: What is pain? What causes pain? Why is it so difficult to treat? To investigate such big-picture questions, Walker focuses on pain at its molecular roots.

"When we feel pain we're not feeling something that's outside of us. It's inside," Walker says. "What we call pain is really a series of chemical reactions happening inside the body. When you touch a hot stove or prick your finger, the body produces molecules that help create the sensation of pain."

For Walker, understanding which molecules are involved with pain, how they work, and how we might be able to alter their behavior are keys to finding better ways to help people cope with chronic, debilitating pain.

What Is Pain?

We all know what pain is. Or, at least, we've all experienced it when we touch a hot stove, get a paper cut, stub a toe, or worse. You can say the same for virtually all living things; poke an amoeba with a microscopic probe, and it flinches.

We can also say with confidence that pain is essential for well-being. Its main evolutionary purpose is to alert us to injury and illness and to warn us away from harmful and life-threatening situations. A case in point: people with a rare genetic disorder called CIPA, or congenital insensitivity to pain without anhidrosis (lack of sweating), often lead short lives. There are stories of children with CIPA walking around with untreated broken arms and legs and other even more serious injuries. Because they're immune to pain, they don't know they're in danger.

On the opposite end of the spectrum, chronic pain can just as decisively curtail a life. Medical literature abounds with bizarre stories of amputees experiencing debilitating "phantom pain" in a lost limb. Despite sophisticated medicines and surgeries, back pain continues to torment millions of people and baffle experts. And for the most part, doctors are lost when it comes to treating chronic pain that has no discernible physical cause.

It's a fact that pain is largely a matter of brain chemistry. Studies have shown that emotional pain--say, pain caused by separation from a loved one or pain related to depression--lights up the same areas of the brain as the pain caused by smashing your thumb with a hammer. As Walker notes, pain affects vast areas of the brain, meaning that it's intertwined with other basic life functions such as breathing and heart rate, and emotions such as fear and anxiety.

So although pain is an elemental part of life, it's also utterly complex. Over billions of years, living things have evolved intricate and many-layered biochemical pathways coded for painful stimuli that scientists are just now beginning to understand. Because pain not only protects life but can also make it unbearable, pain research has attracted an ever-increasing number of scientists intent on unlocking pain's secrets and giving doctors and patients better ways to control its effects.

Molecular Mechanisms

Walker is well aware of how his laboratory work could have ramifications beyond academe.

"Pain is experienced alone but its damage spreads through our society, which must contend with its results and try to contain the cause," Walker writes on his Web site ( "Pain kills individuals by stressing the body past its limits, sometimes by destroying its reserves, sometimes by the despair it brings and the drugs and alcohol that offer respite. It kills human resources and their potential and drains families and institutions of their wealth."

For Walker, learning to control pain instead of being at its mercy means starting at the molecular level where, for all intents and purposes, the sensation we experience as pain originates. There are potentially hundreds, perhaps even thousands, of molecules that play roles in causing and blocking pain, only a few of which scientists have discovered. At the moment, Walker's research breaks down into roughly three areas: how molecules called endocannabinoids inhibit pain, how another molecule called NADA causes burning pain, and the relationship between pain and specialized fat particles known as lipid signaling molecules.

Endocannabinoids, as the name suggests, are marijuana-like substances. But instead of being cultivated secretly under grow lamps in a closet, endocanna-binoids are produced naturally in our bodies. Walker's research has shown that endocannabonoids combine with other molecules to deaden pain. Here's how it works: When you stub your big toe, nerve endings activate and send chemical messages to the spinal cord. The signals are then routed toward the brain, where axons--spindly projections branching out from brain cells, or neurons--pick up the signals and process them as pain. (Because the big toe is so far away from the brain, it can take a second or two after the initial stubbing before the pain actually registers.)

Neurons aren't simply passive receivers. Some produce endorphins--morphine-like opioid substances that kill or lessen pain. Neurons release these natural opiates especially during moments of stress or significant bodily trauma, which helps explain why soldiers sometimes claim to feel little or no pain upon being shot.

What Walker has found is that endorphins are not alone. Neurons also produce endocannabinoids that appear to work alongside the brain's natural opiates. What's intriguing is the possibility of developing synthetic cannabinoids as an alternative to morphine-based pain treatments. Morphine has a proven track record as a painkiller, but, like other opiates, it's also highly addictive and comes with a bevy of unpleasant side effects, including nausea, drowsiness, constipation, and hallucinations. Cannabinoid drugs, like marijuana, are not addictive and cause far fewer and less severe side effects. But for reasons that frustrate many medical scientists, Walker included, cultural stigmas against marijuana have caused pharmaceutical companies to shy away from developing cannabinoid-like drugs.

"Ironically, endocannabinoids bind to the same brain cell receptors as morphine and a lot of psychiatric drugs like Prozac," Walker says. "There are so many instances where commercially available drugs don't work to control pain, but we continue to deny terminally ill patients a compound that's never been associated with death due to overdose and that has no known lasting effects on the body."

Walker's discovery that endocannabinoids help control pain led him to wonder if other molecules may play similar roles. One problem with looking for specific molecules is that they're so incredibly small. But advances in a technology called mass spectrometry, which is used to detect chemical compounds in tiny amounts, has made it possible for scientists to sniff out many previously unknown molecules.

Walker has used this technology to identify several new pain molecules. One of the most interesting is called NADA, a compound similar to capsaicin--the ingredient in chili peppers that makes them so hot to the bite. Injecting even a tiny amount of NADA into human skin, Walker found, causes burning pain.

"Could it be that NADA or a similar substance produces the burning pain of inflammation?" he asks. "That's a question we are trying to answer now."

Walker has also used mass spectrometry to begin to solve another mystery. Drugs, including pain-killing drugs, work by binding to receptors on brain cells. The human genome project has revealed that there are many receptors in the brain that have no known purpose, and Walker suspects that these so-called "orphan receptors" may play an important role in pain management.

To find out, he's used mass spectrometry to study lipids, or fat molecules, in the brain. Lipids are significant because they're so numerous in the brain. In fact, 80 percent of the dry brain consists of lipids, and some of those are known to bind to neurons at receptor sites involved with pain. Could there be many more lipids that bind to those mysterious orphan receptors? Could at least some of the orphan receptors be active in producing or cutting off pain signals in the brain?

That's what Walker is attempting to figure out. If he's successful, the discovery of new molecules associated with pain could open entirely new lines of research for scientists and perhaps lead to new and more effective pain-killing drugs.

A Long Way to Go

Over the past several decades, pain has rocketed to the top of the neuroscience and medical science research hierarchy. Researchers are scrutinizing pain neurons from every possible angle, while drug companies are throwing billions of dollars into drugs that target newly discovered pain receptors. In short, we know more about pain and how it works now than at any other time in history.

Yet, Walker says, what we know is dwarfed by what remains to be known. Part of the problem is that pain works in the body through many simultaneous and redundant pathways. "If you knock out one pathway for transmitting pain signals, another takes over," Walker says. "Even if you come up with a drug that shuts down several pathways at once, there's almost always another that kicks in."

Further complicating matters, pain seems to work differently in animals used to test pain drugs than it does in humans. Experimental painkillers that work wonders in animals have not worked nearly so well in people. The only way to tell if a new drug works is to test it in people--a difficult, heavily regulated process that normally takes many years to yield results.

So despite the combined efforts of many of the world's best scientists, relatively little progress has been made on solving the pain puzzle. The most common drug used to treat serious pain is still morphine--a remedy that has been used for thousands of years. "The fact that we still rely so heavily on morphine tells us that we haven't come close to really solving the problem of pain," Walker says. "We have a long way to go, but we have to keep going because too many people are suffering terribly.

"Is there a magic bullet out there? I don't know," he continues. "We're still trying to understand the variety of molecular events that take place during pain so we can rationally take on the challenge of attacking pain. There are many parts to the biochemical puzzle of pain, many players about which we know almost nothing. If we can get all the players, what they are, and how they operate, we'll have a much better chance of understanding pain as something we can predict."

It's the human factor that drives Walker, the reality of pain not as an academic riddle to be solved but as a very real phenomenon affecting the lives of millions of people. And although answers remain elusive, he's determined to continue exploring the most basic elements of pain.

Jeremy Shere is a freelance writer in Bloomington, Ind.