Origins of ache: immune proteins may yield chronic-pain clues.

In people with chronic pain that has no obvious cause, chemical messengers that rev up or slow down inflammation are often out of balance, a new study finds. These proteins, called cytokines, are made predominantly by immune cells.

Millions of people have chronic pain without any known injury or disease, a condition sometimes called fibromyalgia syndrome. Diagnostic tests are unreliable and treatments are often unsatisfactory, says Claudia Sommer, a neurologist at the University of Wurzburg in Germany. To assess whether cytokines influence such chronic pain, she and her colleagues identified 40 people who had endured unexplained chronic pain for an average of 14 years. Most had symptoms that fit the description of fibromyalgia.

The scientists compared blood samples from these patients with samples from 40 people without pain who matched them in age and gender. All the people--with or without chronic pain--had similar complements of three inflammation-causing cytokines, says Sommer.

However, the team found that compared with the others, the people with chronic pain were low on two anti-inflammatory cytokines: interleukin-4 and interleukin-10. The scientists next enlisted 15 more people with chronic pain who were taking pain medications different from those taken by the first 40 patients. The new group showed the same shortages of interleukin-4 and interleukin-10 that the original group of pain patients showed. The findings appear in the August Arthritis & Rheumatism.

Chronic pain can be impervious to treatment with many analgesics, including narcotics. Some research has suggested that interleukin-4 regulates cells' capacity to display receptors for morphine, codeine, or other opioids.

"It is possible that the patients we examined ... have a lack of opioid response through [this] mechanism," Sommer says. "This is, however, speculation."

Other research suggests that inflammation distorts sensory processing. In animal tests, inflammation has affected the behavior of nervous system cells called glial cells. These cells maintain critical junctions, or synapses, where sensory neurons deliver signals from the periphery of the body to the spinal cord. "Glial cells are in an ideal position to modify neuronal functions [because they] encapsulate the synapses at the terminals in the spinal cord," says Erin D. Milligan, a psychologist and neuroscientist at the University of Colorado at Boulder.

In a state of chronic inflammation, glial cells "get excited and work against the system," she says. Overwrought glial cells induce neurons to transmit or maintain pain messages even when the initiating stimulus is no longer present. They can also oversensitize the nervous system so that a mild touch registers as painful, Milligan says.

Whether a shortage of interleukin-4 and interleukin-10 sabotages nerve terminals in people is unclear, she says, since the authors of the new study didn't measure all cytokines that might have an effect. But the new finding "provides a novel approach for drug development," she says. Boosting concentrations of interleukin-4, interleukin-10, or other anti-inflammatory cytokines in the spinal cord might relieve pain.

The new report describes "important preliminary work that needs to be followed up," says rheumatologist Daniel J. Wallace of Cedars-Sinai Medical Center and the University of California, Los Angeles School of Medicine. Wallace suggests that if researchers do biopsies of chronically painful spots in people's bodies and look at the cytokines there, the scientists might demonstrate an even stronger link between the scarcity of certain cytokines and pain.