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Biological Chemistry

Ugly Ducklings

Naked mole-rats may resemble hot dogs with teeth, but pain researchers still find them attractive

by Rachel Sheremeta Pepling
January 7, 2004 | A version of this story appeared in Volume 82, Issue 2

This juvenile mole-rat may hold the key to pain treatment.
This juvenile mole-rat may hold the key to pain treatment.

Naked mole-rats (Heterocephalus glaber) lack hair, sight, and, quite frankly, good looks. They also lack a common body chemical in their skin, and that may offer clues to pain relief.

Like many discoveries, this one occurred by accident. Thomas J. Park, associate professor of biological sciences at UIC and principal investigator, knew from previous studies that naked mole-rats orient themselves quite well by touch, perhaps as a replacement for vision and hearing--senses not necessary in their native subterranean environment. Naked mole-rats, indigenous to Africa, rarely venture from their burrows. Park's team was looking for clues, such as an abundance of nerve endings, to explain the mole-rats' sensitivity to touch. Routine tests to classify nerves in skin samples yielded unexpected results.

"We were a little disappointed to find that their skin looks fairly normal--until we discovered that instead of having something additional, they actually were missing something," Park says. The researchers ran the tests several times to confirm that Substance P was indeed missing.

Coinvestigator Ying Lu, assistant professor of anesthesiology at UIC, presented the findings last November at the Society for Neuroscience's annual meeting in New Orleans.

To test naked mole-rats' sensitivity to painful stimuli, the team used a heat lamp with a slide projector bulb as a heat source. Heat produced by the bulb was calibrated to about 45 °C, which Park describes as the border between "warm" and "painfully hot." Any temperature above 45 °C would start to damage skin.

Normally, applying capsaicin to an animal's skin increases sensitivity to a heat stimulus. However, when Park applied capsaicin to a naked mole-rat's paw and then exposed the paw to the heat lamp, the animal did not respond at all.

Park's group then introduced Substance P to the naked mole-rats by applying a nonreproductive herpes simplex I virus to one paw. The virus enters nerve endings in the paw and migrates up the nerve fibers. The virus carries the DNA to produce Substance P, which can then be released into the spinal cord when nerve cells are stimulated with painful stimuli.

Park tells C&EN that it was a "really big shock" when his team applied the heat stimulus after introducing Substance P. "We were hoping to see something, maybe a slight increase in sensitivity, but we were really surprised when we found out that after introducing this one neurotransmitter, all of a sudden these animals behaved just like all the other animals that had been tested."

One theory has to do with the naked mole-rat social structure. Naked mole-rats live in colonies consisting of a breeding queen and many workers, much like the colonies of bees, ants, and wasps. In such a tight community, infighting would be counterproductive. The lack of Substance P could be an adaptation to eliminate aggressive individuals from the population. Since naked mole-rats can't detect wounds due to the absence of Substance P, aggressive individuals would be more likely to die from infections from bites and scratches.

Park has another theory, also related to their communal society. Naked mole-rats live underground in tight spaces, often in colonies of 100 or more individuals. Park suspects that in such conditions, CO2 from breathing accumulates to a high level often painful to mucous membrane tissues such as the lips, nostrils, and eyes. This type of pain is signaled by Substance P. To avoid living in constant pain, the naked mole-rats may have evolved to eliminate the neurotransmitter. To test his theory, Park hopes to go to Africa to measure CO2 levels in natural naked mole-rat burrows.

David C. Yeomans, associate professor of anesthesia and director of the Pain & Analgesia Research Center at Stanford University, says the results from Park's study could prove valuable. "They've been able to provide some very important information that adds to the ongoing debate about the importance of Substance P in pain," he says.

For instance, results from Park's study could help lead to therapies for chronic pain conditions such as fibromyalgia. Research indicates that one possible cause of fibromyalgia is too much Substance P in the nerves.

"These animals have evolved some way of modulating the levels of Substance P for whatever benefit to them. If we can learn from them how they did that biologically, it could help us develop new treatments," Park says.

Yeomans agrees that Park's results could lead to new treatments for certain types of chronic pain like fibromyalgia. Yeomans says pharmaceutical companies have previously developed drugs that block Substance P, but the drugs had little effect on pain in clinical trials. He suspects the trials were targeting the wrong type of pain. "This type of result may push the pharmaceutical companies to look a little harder or a little more cleverly at what types of pain they should try to treat with Substance P-blocking drugs," he says.

If researchers are successful in using naked mole-rats as a tool for new treatments, then these ugly ducklings will turn out to be the beautiful swans of the pain research community.



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