The naked mole-rat is not your typical rodent. It’s cold-blooded, lives for decades, and does not experience some kinds of pain. Gary Lewin and colleagues at the Max Delbrück Center for Molecular Medicine in Berlin, Germany, now find that tweaks to a single molecule, called the TrkA receptor, can explain how the animal fends off pain, in particular the exaggerated sensitivity to heat resulting from inflammation.
When a tissue becomes inflamed, cells there release a number of molecules, including one called nerve growth factor (NGF). Within minutes, NGF “sensitizes” another molecule, TRPV1, which forms a pore through the cell membrane of the nerve cells that send pain signals.
Typically, this pore stays closed. But with excessive heat, it opens. Electrically charged molecules outside nerve cells then rush in, and as a result, pain signals are produced. So, in its more sensitive state, TPRV1 makes painful heat that much more intense.
The researchers show that in neurons from naked mole-rats, NGF cannot sensitize TRPV1. The problem lies not with TRPV1 itself, but rather with the TrkA receptor, a protein to which NGF binds and activates in the process of heightening pain sensitivity. The investigators estimate that between one and three changes in the TrkA molecule make it less able to sensitize TRPV1.
Peter McNaughton, King’s College London, UK, says that the study is “an interesting examination of the molecular basis of one form of pain sensitization in a strange African species, the naked mole-rat.” He suggests that finding out why this molecular signal has been disabled in the naked mole-rat might open up ways of blocking it in human conditions where pain arises from inflammation, as in osteoarthritis.
The findings were published online October 11 in the journal Cell Reports.
Small change, big effect
It was by serendipity that Lewin began studying pain in naked mole-rats. In 2002, he was introduced to Thomas Park, a researcher at the University of Illinois at Chicago, US, who was studying naked mole-rats for completely different reasons. Park, however, discovered that these rodents had a dearth of pain nerve fibers in their skin, suggesting that they might not experience pain in the same way as other mammals.
Years later, Lewin and Park together showed that naked mole-rats shrug off painful chemicals such as acid. And, they don’t become sensitive to heat either during inflammation or after NGF is given. In 2011, Lewin pinned the acid resistance on a variation of one protein. But that left the question of how evolution had done away with the hypersensitivity to heat.
To look for answers, Damir Omerbašić and Ewan Smith, the lead authors of the study, and their colleagues studied pain-signaling neurons near the spinal cord that they isolated from naked mole-rats, and from mice. These neurons transmit pain signals from the body into the spinal cord, where they are ultimately relayed to the brain.
The authors reasoned that because heat hypersensitivity depends on NGF and how it sensitizes TRPV1, studying that process would reveal a culprit for the loss of pain. So they recorded the flow of electrical current through TRPV1 in the neurons they had isolated. Rather than opening the pore with heat, they used capsaicin, the component of chili peppers that causes a burning sensation. Neurons from mice responded to capsaicin, and did so even more after NGF was applied to them. But that sensitization was absent in neurons from naked mole-rats.
As for why, the researchers went on to show that TrkA, not TRPV1, had been changed. Compared to five other mole-rat species, between one and three amino acids—the building blocks of proteins—were different in TrkA of naked mole-rats. “What surprised us was how small the change could be,” says Lewin.
The study is “very well-performed,” says McNaughton, “and the conclusions are well supported by the data.”
To learn more, Lewin and his colleagues are now making genetically engineered mice that will be more similar to naked mole-rats. Specifically, they are switching out the three relevant amino acids in the mouse version of TrkA for those from naked mole-rats. Lewin predicts that when given NGF, these mice will not respond to extreme heat as they would otherwise.
For Lewin, TrkA in the naked mole-rat is another example of how evolution can validate the pain field’s main strategies to relieve pain. Drugs targeting the molecule responsible for the rodent’s acid insensitivity—a protein called Nav1.7—have looked promising in clinical trials. And while not as far along, researchers are also developing inhibitors for TrkA.
“Evolution chose the TrkA receptor to fiddle with before we had an idea of what TrkA was,” Lewin said. –Matthew Soleiman
To read about the research in more detail, see the related Pain Research Forum news story here.
Matthew Soleiman is a science writer currently residing in Nashville, Tennessee. Follow him on Twitter @MatthewSoleiman.