Although it has a face—and body—that only a mother could love, the naked mole rat has a lot to offer biomedical science. It lives 10 times longer than a mouse, almost never gets cancer, and doesn’t feel pain from injury and inflammation. Now, researchers say they’ve figured out how the rodents keep this pain away.
“It’s an amazing result,” says Harold Zakon, an evolutionary neurobiologist at the University of Texas, Austin, who was not involved with the work. “This study points us to important areas … that might be targeted to reduce this type of pain.”
Naked mole rats are just plain weird. They live almost totally underground in colonies structured like honey bee hives, with hundreds of workers servicing a single queen and her few consorts. To survive, they dig kilometers of tunnels in search of large underground tubers for food. It’s such a tough life that—to conserve energy—this member of the rodent family gave up regulating its temperature, and they are able to thrive in a low-oxygen, high–carbon dioxide environment that would suffocate or be very painful to humans. “They might as well be from another planet,” says Thomas Park, a neuroscientist at the University of Illinois, Chicago.
Gary Lewin, a neuroscientist at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association in Berlin, began working with naked mole rats because a friend in Chicago was finding that the rodent's pain fibers were not the same as other mammals'. In 2008, the studies led to the finding that naked mole rats didn’t feel pain when they came into contact with acid and didn’t get more sensitive to heat or touch when injured, like we and other mammals do. Lewin was hooked and has been raising the rodents in his lab ever since. They are a little more challenging than rats or mice, he notes, because with just one female per colony producing young, he never really has quite enough individuals for his studies.
So instead of studying the whole animals, he began isolating single nerve cells from the mole rats and investigating them in lab dishes to track the molecular basis of the rodent’s pain insensitivity. The pain pathway is kicked off when a substance called nerve growth factor is released by injured or inflamed cells. This factor binds to a protein on the pain-cell surface, a so-called receptor named TrkA, which relays the “pain” message throughout the cell. In us and other mammals, that message increases the activity of a molecular pore, called the TRPV1 ion channel, causing the cell to become more sensitive to touch or heat. “So the cell says ‘It hurts more,’” Lewin explains.
But that doesn’t happen in naked mole rats. Lewin evaluated the workings of the animal’s pain pathway components by mixing them with those of standard rats and putting the combinations in immature frog eggs. For example, the naked mole rat TRPV1 channel sensitized the egg to acid and heat when the rat TrkA was put into the egg cell with it. Thus, Lewin and his colleagues narrowed down the breakdown in this pathway to the TrkA receptor itself. The naked mole rat version of TrkA failed to activate the ion channel as efficiently as the rat version of TrkA, Lewin and his colleagues reveal today in Cell Reports.
When they compared the amino acid sequence of naked mole rat protein, the researchers found that three of these protein building blocks were different from the rat version and one was also different from the same protein in other mole rats. That particular difference made the naked mole rat receptor inefficient at relaying the pain sensitization signal.
Similar defects are seen in people, says Clifford Woolf, a neuroscientist at Boston Children’s Hospital and Harvard Medical School who was not involved with the work. But contrary to the portrayal of the unstoppable blond giant in The Girl Who Played with Fire, a mystery thriller by Swedish writer Stieg Larsson, “if an individual has mutations that reduce the capacity to feel pain, that’s extremely dangerous,” Woolf says. “It’s not a relief from pain; it’s a disaster,” because the body cannot detect when it's hurt.
But for naked mole rats, this drop of efficiency likely represents a good compromise, Lewin explains. Nerve growth factor and the receptor are important to the proper development of the nervous system. Thanks to this less efficient, albeit still functioning, receptor, the naked mole rat still winds up with an adequate nervous system, but with fewer pain nerve cells. That, in turn, could reduce the energy the animal needs to fuel its nervous system, likely useful in an environment where starvation is common and the body wants to conserve energy. “This illustrates how big steps in evolution can sometimes proceed from a single small mutation,” Zakon says.
The naked mole rat work could inspire better pain treatments. “Traditional medical interventions for pain have frequently attempted a brute force approach, which can cause unintended bad side effects,” Park says. For example, neurologists have tried pain drugs that neutralize nerve growth factor and control pain without the use of opioids, say in arthritis. But sometimes the treatment leads to damage to the knee joint. “Using what has been learned from the Lewin paper,” it might be possible to tweak the receptor for nerve growth factor to limit this side effect, says Lorne Mendell, a neuroscientist at the State University of New York at Stony Brook.