New views of what causes pain and keeps it going, along with advances in clarifying genetic, psychological, and gender influences on the pain response, may benefit persons with chronic pain from cancer, fibromyalgia, diabetes, amputations, and other illnesses and injuries, according to speakers at the annual meeting of the American Association for the Advancement of Science in Washington, D.C., in February.

A permanent injury such as a limb amputation changes the nervous system, said Allan Basbaum, M.D., professor and chair of anatomy at the University of California, San Francisco. Persistent pain is a disease itself, he asserted, not merely a symptom of an underlying disorder.

The discovery that some nerve cells associated with the pain transmission system, such as the capsaicin receptor, express unique classes of molecules has brought molecular biologists into the field and identified new therapeutic targets.

"If you have a unique target," Basbaum observed, "you can treat the problem without wide-ranging side effects. There are no acute or chronic pain pathways." But injury alters some signal transmission, leading to conditions in which normally innocuous stimuli cause pain. In effect, he said, "there is a volume gain at the level of the spinal cord." By targeting the mechanisms through which this amplification process occurs, he said, it may be possible to reduce abnormal pain states selectively, without affecting acute pain processing.

New research in genetics aims to identify the "volume knob," said Jeffrey Mogil, Ph.D., a professor of psychology and neuroscience at the University of Illinois at Urbana-Champaign. Mogil’s work focuses on localizing genes involved in pain and opioid analgesic sensitivity, especially those involved in producing individual differences.

About 50 percent of the variability in animal studies, he said, can be attributed to genes. "When studying inherited traits in inbred mouse strains, in which mice are virtual clones of each other," Mogil said, "any differences you see within strains must be environmental. Any differences between strains are likely genetic."

The same degree of sunburn may cause more or less pain to different people. "The discovery of variability," Mogil said, "may show that whiners really are feeling more pain, and stoic people may not be having such severe pain."

Catherine Bushnell, Ph.D., a neuropsychologist who holds the Harold Griffiths Chair in Anesthesia at McGill University, Montreal, Canada, uses functional magnetic resonance imaging to assess the neural networks that underlie the experience of pain. While individuals show different patterns, she said, there are some commonalties in the cerebral cortex and the limbic system.

When people experience allodynia, or severe pain in response to light stroking, abnormal activation patterns occur. These involve activation of pain-related areas of the cortex on both sides of the brain. Related studies of phantom limb pain in Germany also suggest the cerebral cortex reorganizes after an amputation in a way that keeps pain going.

A person’s emotional state also affects the perception of pain, she said. Someone with intestinal cancer likely will find stomach pain more worrisome than someone who attributes the pain to indigestion. If a person is distracted, pain usually is perceived as less severe. Distraction modulates pain-related activation in both sensory and limbic regions of the cerebral cortex, she said, just as if the person had received an analgesic. It also reduces activation in the limbic system. "It’s important for physicians to know," Bushnell said, "that patients have some control over their pain."

In her studies, Bushnell uses two types of stimuli to produce distraction: pairs of heat stimuli that create a burning sensation without damaging the skin, and pairs of tones presented through earphones while the volunteer is in an MRI scanner. In both situations, the subject is asked to assess which of two stimuli is more intense.

Hypnosis can change the emotional experience conveyed by pain, she said, without affecting the actual sensation. Subjects given hypnotic suggestion in her studies had a lowered response to pain one week later. The studies suggest that distraction can activate intrinsic pain-inhibition circuits in the brain to relieve pain. The pain signals were dampened before they reached the cortex, Bushnell said, adding, "We weren’t just teaching patients to report pain differently."

Gender also may influence how people respond to pain, speakers said. Women both report lower thresholds for heat pain and display greater activity in the brain. Pain responsiveness also varies over the menstrual cycle. Women perceive the same pain stimuli as more painful in the late-luteal phase, just before or at the time of menstruation. Symptoms of many chronic illnesses also flare at this time of the cycle.

Overall, about half of pain response studies show gender differences, Mogil said. The magnitude of these differences depends on the type of pain stimulus applied, the intensity of the pain, and other factors.

"What’s interesting is not that men and women aren’t completely equal in their pain sensitivity," he said, "but rather that they process pain using different neural circuitry."

The gender difference in humans, Mogil speculated, may reflect an evolutionary adaptation. Since the earliest humans were hunter gatherers, Mogil said, men may have evolved to avoid the pain of trauma such as lion bites and spear points, while women may not have.

It eventually may be possible to use DNA markers of variability, Mogil said, to predict how specific persons will respond to pain-relieving medications from acetaminophen to morphine. About 7 percent of the population, for example, have trouble converting codeine to morphine. Without that conversion, codeine does not relieve pain. A test that identifies those persons would be too costly to be practical today, but such tests, he said, might aid physicians in prescribing in the very near future.