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A team of neuroscientists at Johns Hopkins offers the first concrete evidence of what's behind some of the most incapacitating pain syndromes people can suffer, a move suggesting immediate strategies for treatment. The syndromes, part of a larger category called neuropathic pain, can occur after the most transient or insignificant injury to a nerve. Over time, pain from the injury extends to nearby skin, which becomes exquisitely sensitive to touch and temperature change. "A mere breeze can trigger severe burning pain, as does going outside on a hot summer day," says neurosurgeon James Campbell, M.D., one of the research team. Changes in skin texture, bone loss or contraction of nearby joints may follow. Neuropathic pain isn't as common as headache or arthritis pain, but neurologists estimate costs worldwide in medical treatment and disability pay run in the millions. The biology of the problem has eluded scientists since it was first well- described a century ago (see enclosed description).
Working with animals, the Hopkins team clearly showed pain signals can originate in nerves not directly at the site of injury. The study, led by Hopkins neurosurgery professor Richard Meyer, M.S., appears in this month's Journal of Neurophysiology. The scientists partially severed a single pain nerve - a step known to produce signs of neuropathic pain -- and then looked at electrical activity in nearby, undamaged nerves leading to the skin.
In the model animals, the researchers report, branches of the damaged nerve completely disappeared. Nearby undamaged nerves were intact, but they now showed abnormal and spontaneous activity -- telegraphing a message of pain.
In a second part of the study, the researchers added adrenalin-like chemicals to the skin to mimic conditions of a specific type of neuropathic pain called sympathetically maintained pain (SMP). In this least well-understood syndrome, a person's adrenalin-releasing sympathetic nervous system -- one involved in "fight or flight" -- somehow links injured pain nerves with noninjured ones. Things that stimulate this nervous system, like temperature changes, also seem to trigger the pain.
"In the study, undamaged nerves not only become active," says Meyer, "but they also fired in response to our adrenalin mimic, something you'd expect in human SMP."
"What we're seeing here," he says, "is a biological change in the innocent' pain nerves whose territory overlaps that of injured nerves. Something makes them newly receptive to, say, adrenalin or, perhaps, to other stimuli such as pressure. Knowing this," he adds," also suggests treatment."
Existing therapy for neuropathic pain centers on drugs such as opiates that affect the brain's perception of pain, but the cost runs high in side effects. Surgery is an option in some patients, "but results are often disappointing," says Campbell. "These new studies, however, show a basis for targeting the skin -- specifically the skin originally served by the injured nerve. The significance," he adds, "is that pain may arise from the affected skin and that therapy directed there may be quite effective."
The research team is already testing ways to block activity in the activated nerves, such as destroying their sensitive endings via large doses of the chili pepper derivative capsaicin, applied to a patient's skin under anesthesia. Also, ointments containing clonidine, which locally blocks the sympathetic nervous system, might take away the trigger for SMP and other kinds of pain.
The research was supported by grants from the National Institute of Neurological Disorders and Stroke. Other researchers were Zahid Ali, Ph.D., Matthias Ringkamp, M.D., Timothy Hartke, Philip Chien, and Nicholas Flavahan, Ph.D.
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