Study Links Abnormal Pain Syndrome To Nerve Cell Changes

March 01, 1999

CHAPEL HILL, N.C. - A study by researchers at the University of North Carolina at Chapel Hill has identified molecular changes in nerve cells that may play an important role in an abnormal pain syndrome that often eludes effective treatment.

The new findings, published March 1 in the Journal of Physiology, adds important new knowledge to the mysterious medical syndrome causalgia and opens the door to finding new ways to treat it.

Causalgia involves the spontaneous occurrence of persistent burning pain that begins days or weeks after traumatic injury to a large nerve, usually in a limb. First described after the Civil War, causalgia can appear after accidental nerve traumas, such as automobile crush injuries and industrial mishaps.

"Typical injuries that have led to the causalgic syndrome are injuries to a large nerve like the sciatic nerve, which runs the length of the leg, or the ulnar and median nerves of the arm. These are large mixed nerves that contain motor and sensory fibers," says Dr. Edward R. Perl, professor of cell and molecular physiology at the UNC-CH School of Medicine.

Perl, a physician and neurophysiologist, is noted for his pioneering work in pain mechanisms. He says a classical hallmark of causalgia pain is its "spontaneous occurrence after a completely innocuous event." Cool air on the skin or light touch can set it off, even worsen it. The pain is also aggravated by emotional upset. Excessive perspiration occurs in the painful area, and the skin becomes discolored and swollen and shows an unusual growth of hair, he explains.

One prominent theory of causalgia holds that the region that lost nerve fibers in the injury becomes "supersensitive" to norepinephrine, a normal body chemical involved in sensory nerve impulse conduction, the UNC-CH study finds.

In their report, Perl and his co-author, Dr. Lori A. Birder, now at Pittsburgh University, discovered that complete or even partial damage to mixed peripheral nerves results in significant increases in certain molecular receptor sites on the surface membrane of neurons. These alpha-adrenergic cell receptors are protein molecules that bind to neurotransmitters, such as norepinephrine and epinephrine. These substances act as chemical messengers to enhance communication between nerve cells.

"In sensory neurons, these alpha-type adrenergic receptors are expressed only in minimal or limited quantity, if at all, under normal circumstances," Perl says.

Moreover, the increased production of these receptors occurs both in sensory nerve fibers affected by injury and those nearby that are intact. Thus, in the days or weeks following an injury, the cellular stage becomes set for a heightened sensitivity and spontaneous activity, which the person perceives as burning pain.

In terms of stopping the pain, limited and mostly temporary success has been achieved by surgical removal of the affected segment of sympathetic nerve or by using local anesthetics as nerve blocks. These procedures reduce norepinephrine within the affected tissue.

Perl notes that one of the tests used to determine which alternative might work best involves intravenous injection of a drug known to block adrenergic receptors. "And this so-called 'pentalomine test' happens to be a blocker of adrenergic receptors of the alpha type," Perl says. "And that sometimes produces a very dramatic relief in these people which outlasts the usually expected action of the drug."

Then why not use the drug as a treatment? "The problem with that drug is that it produces a block of sympathetic, or involuntary, control of blood vessels. This produces a drop in blood pressure low enough to impair a person's activity, including walking," Perl says.

"Perhaps a more selectively acting adrenergic blocker can be developed," he adds.
Note to reporters: Dr. Edward R. Perl can be reached at 919-966-3560, or email UNC-CH School of Medicine media contact is Lynn Wooten, 919-966-6046, or email

University of North Carolina at Chapel Hill

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