Contacts:
Patrick Mantyh, University of Minnesota School of Dentistry, (612) 626-0180
Deane Morrison, University News Service, (612) 624-2346, [email protected]
Special class of pain nerves identified by researchers at
U of Minnesota; finding holds hope for chronic pain relief
One of the biggest hurdles for doctors of burn victims is finding a way to treat the patient when every little touch sends waves of agony through the patient's body. This kind of reaction isn't limited to burned tissue; hypersensitivity to normally benign stimuli is typical of many patients suffering from chronic pain. For example, arthritis sufferers feel sharp pain from routine joint movements, and cancer patients become hypersensitive to movements and touches that didn't bother them before. In the treatment of chronic pain, hypersensitivity caused by tissue injury ranks as a major obstacle.
In a step toward providing relief, researchers at the University of Minnesota and the Minneapolis Veterans Administration Medical Center have identified a group of nerves that are instrumental in causing hypersensitive pain responses. Working with rats, the researchers showed that destroying a certain type of spinal nerve left the animal resistant to a treatment that usually causes hypersensitivity to heat and touch. The work will be published in the Oct. 10 issue of Science.
"We're beginning to uncover the chemistry of pain at a level we never understood before," said lead investigator Patrick Mantyh, a researcher at the VA Medical Center in Minneapolis and the University of Minnesota's School of Dentistry and department of psychiatry. "It shows that there's an extremely small population of cells--no more than one percent of spinal nerves--that plays a pivotal role in the generation of chronic pain."
In knocking out the nerves responsible for hypersensitivity, the researchers used a "smart bomb" technique that "fooled" those nerves into absorbing poison but left other nerves intact.
The researchers worked with a group of spinal nerves that had one thing in common: They were the only ones that could snag, and ingest, a small protein molecule called substance P, which is known to be involved in pain signalling. The cells snag substance P and pull it out of the surrounding cerebrospinal fluid by means of large molecules on their outer surfaces. These molecules, called substance P receptors, act as magnets that grab and hold substance P and nothing else. Once substance P has been captured, it is ingested by the cell, receptor and all.
Mantyh and colleague Don Simone reasoned that if a poison could somehow be attached to the substance P, it, too, would be drawn into the cell. The poison had to be small enough to be taken into the nerve cells but potent enough to kill them. Such a chemical was supplied by Douglas Lappi at Advanced Targeting Systems in San Diego, who provided Mantyh's team with a compound consisting of substance P coupled to saporin, a chemical that prevents cells from making protein. When injected into the cerebrospinal fluid of rats, the substance P-saporin compound was absorbed by cells possessing the substance P receptor. Within four days, the saporin had killed those cells.
Mantyh's team then tested the ability of rats treated with substance P-saporin to become hypersensitive to heat and touch. In a normal rat, an injection of capsaicin--the active ingredient in hot peppers--under the skin of a paw makes the paw temporarily hypersensitive. The researchers placed the paws of normal rats and substance P-saporin-injected rats on a very warm plate; both groups of rats withdrew their paws after about 12 seconds. When the two groups of rats received subdermal injections of capsaicin in their paws, the normal rats removed their paws from the plate after only 4 seconds, but the substance P-saporin rats left theirs on the plate for the full 12 seconds. Similarly, normal rats react negatively to light stroking on capsaicin-treated paws, but the substance P-saporin rats did not. Thus, the substance P-saporin rats appeared protected from hypersensitivity to heat and touch.
"This treatment signals a revolution in pain research," said Mantyh. "Currently, treating chronic pain usually involves introducing opiates into the bloodstream, and they get into all cells of the body, leading to side effects such as sedation, constipation, tolerance and addiction." But Mantyh's therapy appears to affect only the cells involved in hypersensitivity--the main component of chronic pain--leaving the rest of the nervous system unaffected.
"It's important to note that the body will still respond to acute stimulation," said Mantyh. "For example, chronic pain patients who received this treatment would still have the reflex to remove their hands from a hot stove, and their nervous systems would still communicate the news of an injury to the body." The difference is that such patients would no longer feel pain from a stove that a healthy person would find tolerably warm.
Mantyh's findings have implications for other types of therapy, he said. For example, gene therapy may be possible by coupling the appropriate gene to substance P and then letting the appropriate nerves ingest the package. The system could also work with other substances and their receptors on the surfaces of other cells. For example, heart cells that respond to adrenalin (and have adrenalin receptors on their outer surfaces) could be coaxed into ingesting a heart drug if it were coupled to adrenalin molecules. In the near future, Mantyh plans to test the substance P-saporin system in tumors of astrocytes, cells that are not nerves but play an important role in nervous system functioning. Those tumors are often carpeted with substance P receptors, and Mantyh hopes to kill the tumor cells by treating them with substance P coupled to an antitumor drug.
"In this approach, the harmful cell selects the lethal compound while the neighboring cells remain intact," Mantyh said. "All cells have receptors similar to the substance P receptors found in the chronic pain cells. If we let the cell do the work of selecting the molecule, we can be infinitely more accurate in targeting cells for therapeutic manipulation."
News releases also on WWW at http://www.umn.edu/urelate/news.html
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