Inflammatory pain may help deter inflammatory diseases like arthritis

August 30, 1999

Pain alerts the body to danger, but UC San Francisco researchers report that it may play another crucial role - helping to prevent the body from slipping into the chronic inflammation associated with such diseases as arthritis, colitis and asthma.

The finding, published in the September issue of Nature Medicine, provides the first evidence -- after years of inquiry -- of an active process controlling inflammation, and may open a new window to understanding the mechanisms at the heart of chronic inflammatory diseases.

People experience pain when signals from specialized nerve fibers are activated. These pain nerve fibers are triggered when tissue is damaged. They are re-activated by inflammation, the body's normally beneficial response to trauma and infection.

Inflammation increases blood flow to the site of injury and sends in a flood of rescue factors - such as substances that clot wounds and white blood cells that chew up invading disease-causing pathogens -to the site. But research has shown that unrestrained inflammation can cause chronic, debilitating diseases.

Traditionally, researchers have thought that the factors involved in the inflammatory response ultimately dissipated on their own. But the UCSF study suggests that activated pain nerve fibers, themselves, dampen the inflammatory response's first line of attack -- a cell known as the neutrophil, which sweeps into an injured site, releasing chemicals that work to heal wounds.

"Our work suggests that pain acts as a negative feedback control of inflammation," said the lead author of the study, Holly Strausbaugh, PhD, a postdoctoral fellow in the NIH Pain Center at UCSF. "Once enough inflammation builds up that pain nerve fibers are activated, the inflammatory response begins to diminish. Failure of this mechanism could contribute to the development of chronic inflammatory disease."

Notably, said Strausbaugh, pain fibers are not activated until the inflammatory response is well under way, which gives the inflammatory response time to mount a powerful attack first. "It's a neat little trick, because some inflammation is good. It just needs to be kept in check," she said. Strausbaugh conducts her research in the laboratory of senior author Jon Levine, MD, PhD, a professor of medicine and oral and maxillofacial surgery and director of the NIH Pain Center at UCSF.

"If we can understand what factors mediate the response we're seeing from the pain circuit -- down to the molecular mechanisms -- then we can eventually start looking in people who have chronic inflammatory diseases to try to see if the mechanism is disrupted there. If we find that it is, we can try to fix it," she said.

As neutrophils play a central role in inflammatory responses throughout the body, the researchers' observation will likely apply to inflammation across the board, said Strausbaugh, though, she added, painful stimuli will likely prove to be one of several factors modulating the inflammatory response.

The researchers conducted their study in anesthetized rats with inflamed knee joints, determining that a painful stimulus applied to the animals' hind paw completely blocked neutrophil accumulation in the animals' joints. Researchers in the Levine lab had previously shown that activated pain fibers in the rats' hind paw caused decreased swelling in the animals' inflamed knee joints. This decrease in swelling, far from the site where the nerve fibers were activated, had indicated that the nerves were exerting their effects through some factor that had access to or could migrate to a different part of the body.

And it was this observation that suggested the possible role of the roving neutrophils.

The current study demonstrated not only that neutrophils were the target of the activated pain nerve fibers, but that the pain fibers acted on these cells through the leukocyte adhesion molecule known as L-selectin. Neutrophils access inflammation by moving from the blood, through the lining of the blood vessels and into the tissue, and they begin this process by adhering to the lining of the blood vessels. L-selectin, expressed on the cells' surface, allows the cells to adhere to and slowly roll along this lining.

The crux of the UCSF finding was determining that activated pain fibers caused L-selectin to be shed from the neutrophils circulating in the blood, thereby preventing the white blood cells from accessing the inflammatory site. The mechanism by which L-selectin shedding inhibited neutrophil migration is not entirely clear, but the shedding did block the migration.

"We still must work out the specific mechanisms involved in this process," said Strausbaugh, "but activation of pain fibers does induce the shedding mechanism and is responsible for the observed inhibition of neutrophil accumulation." The researchers must also determine what hormone messenger is released into the blood in response to activity in pain nerve fibers to cause L-selectin shedding in the first place. The answer could lead to a future therapy.

"It may be that insufficient amounts of the hormone are released, or that receptors for the hormone are defective," said Strausbaugh. "If the problem was that the amount of the hormone was insufficient, therapy might be as simple as injecting the hormone into the blood stream."

Alternatively, she said, some people might have a defect in the pain nerve circuit that either prevents the pain fibers from being activated or that activates them too late.

Already, the finding is offering important insight into studies recently reported in humans. One investigation, conducted in patients with adult respiratory distress syndrome, associated with chronic bronchitis, asthma and emphysema, (Lancet, 344, 215-9, 1994), showed that patients who had low levels of L-selectin in the blood were sicker and died more often. As low levels of L-selectin in the blood indicate that few L-selectin molecules have been shed from neutrophils, the patients' poor condition could be explained in part by the fact that neutrophils continued to accumulate at the site of injury, prolonging the inflammatory response, said Strausbaugh.

"We're very excited about the direction of our research," said Strausbaugh. "Our finding provides quantifiable evidence that the pain circuits are involved in controlling inflammation."

Other co-authors of the study included Paul G. Green, PhD, an adjunct assistant professor of oral and maxillofacial surgery, Ernest Lo, MS, a student, David B. Reichling, PhD, an assistant research physiologist at the NIH Pain Center at UCSF, Kirsten Tangemann, PhD, a postdoctoral fellow in the Department of Anatomy and Program in Immunology at UCSF, and Steven D. Rosen, PhD, a professor, in the Program in Biomedical Sciences and the Department of Anatomy and Program in Immunology at UCSF.

The UCSF study was funded by the National Institutes of Health.

University of California - San Francisco

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