The naked mole-rat is impervious to certain kinds of pain. Its not alone | NOVA

With its loose, bunchy skin and sun-starved complexion, the naked mole-rat (Heterocephalus glaber) recalls an uncooked bratwurst dried on permanent press—and it might be one of the last creatures you’d expect to have superpowers.

But scientists have known for years that these wrinkly wonders boast an astounding set of death-defying qualities: They live decades longer than other rodents, almost never get cancer, and can survive without oxygen for more than 18 minutes. They’re even impervious to certain types of pain.

Now, new research suggests that some of these rodents’ oddball characteristics may not be as unusual as once thought. According to a study published today in the journal Science, the inability to feel pain is something of a family trait—one that runs rampant across the mole-rat phylogenetic tree.

But for these rodents, the evolution of a pain-free existence comes with a twist. Rather than being passed down in carbon copy as mole-rats split off into separate species, resistance to pain seems to have arisen independently in separate lineages—and it doesn’t always manifest in the same way. While some species of these subterranean critters live in blissful ignorance of the sting of acid burns, others are immune only to acrid substances commonly found in plants.

“This is a fabulous study and a very thorough investigation,” says Rochelle Buffenstein, a biologist studying naked mole-rats at Calico Labs in San Francisco who was not involved in the study. “The researchers have provided a little window into how these animals are able to shut down different kinds of pain in different situations.”

For all its simplicity, the word “pain” encompasses an awful lot. Many different flavors of unpleasantness exist, but one of the body’s most important pain-sensing systems exists solely to detect the types of dangerous chemicals that tend to lurk in snake venom or poisonous shrubs.

This makes it all the weirder that the naked mole-rat can’t feel two pretty universally agonizing kinds of chemicals: acid and capsaicin (the spicy substance that gives chili peppers their heat). Though the reason behind these insensitivities hasn’t been completely worked out, it probably has something to do with these rodents’ underground habitats, where they’re exposed to a bevy of extreme conditions. Here, adaptations that eased the nuisance of pain could be a way to make a tough life more bearable.

Naked mole-rats, however, aren’t the only rodents tunneling in the sands of sub-Saharan Africa. Dozens of other African mole-rat species exist, each with its own unique environmental quirks—but no one had ever tested whether the naked mole-rat’s closest cousins shared its insensitivity to pain.

So a team of researchers led by Gary Lewin, a molecular physiologist at the Max Delbrück Center, decided to construct a family tree of mole-rat pain tolerance. After amassing nine evolutionarily distant species of African rodents (including the OG naked mole-rat), the team injected the rodents with three odious chemicals: dilute hydrochloric acid, capsaicin, and allyl isothiocyanate (AITC)—the sinus-clearing compound that gives wasabi and horseradish their pungent taste.

Right off the bat, it was clear that pain tolerance was not a universal mole-rat attribute. Like their distant mouse relatives (and humans, for that matter), four out of nine rodent species expressed discomfort in the presence of all three chemicals. Of the five remaining, two species, the Cape mole-rat (Georychus capensis) and the East African root rat (Tachyoryctes splendens), had no response to hydrochloric acid, while another, the Natal mole-rat (Cryptomys hottentotus natalensis), was insensitive to capsaicin. As before, the naked mole-rat was indifferent to both. Oddly, pain sensitivity combinations didn’t match up by relatedness, suggesting that several lineages had found their own way to the same pain-free outcome.

Every species tested, however, had a strong reaction to AITC—a compound known for its destructive powers in most animal bodies—except for one: the highveld mole-rat (Cryptomys hottentotus pretoriae), which became “the star of this particular study,” Lewin says. “This insensitivity [to AITC] is, as far as we know, completely unique in the animal kingdom.”

To track down the basis of this enigmatic trait, Lewin and his team extracted and compared genetic material from all nine species. The analysis revealed two subtle differences in the highveld mole-rat. One was a mutation in a gene that made AITC tougher to detect. Another boosted the expression of a protein that jettisoned signaling molecules out of pain receptive cells, compromising their ability to relay the presence of AITC.

But neither of these alterations had completely removed the AITC detection system from the highveld mole-rat. The genetic hardware was still in place—the lines of communication had just been gummed up. When the researchers next treated the rodents with a chemical that plugged up the protein that made pain receptive cells leaky, they became just as sensitive to AITC as their horseradish-hating cousins.

A drug that did the exact opposite of this and increased the leakiness of the protein could someday have value as a therapy for chronic pain, Lewin says.

It’s still unclear why only the highveld mole-rat has adopted AITC insensitivity, but as with its cousins, the trait is probably a product of its unusual lifestyle, says study author Ole Eigenbrod, who completed his PhD in Lewin’s lab. It’s possible these rodents have become tolerant to AITC to cope with the spicy roots in their diets, or the stinging bites of the Natal droptail ants that frequent highveld hovels.

A pain-free coexistence with ants could confer “a huge advantage” on highveld mole-rats, which would be able to populate areas without any challenge from other rodent species, which are presumably sensitive to the insects’ nips and nibbles, Lewin says. It’s even possible that highveld mole-rats have expanded the typical vegetarian palate of their kin to include these ants, which could be a serious perk in times of scarcity.

That said, there are trade-offs to any kind of pain tolerance—and it remains to be seen what cost the highveld mole-rat may be paying for these ant-ics. There’s probably a reason researchers haven’t yet found a mole-rat—or any other animal—that’s completely impervious to all three of these painful chemicals, says Elena Gracheva, a neuroscientist at Yale University who was not involved in the study. (Were that hypothetical animal to be discovered, though, it would still presumably be vulnerable to myriad other types of pain, including cold burns and the agony of flesh wounds.) Pain, after all, is a memorable tutor—and a life without clear signs of danger would probably be a short one.

But the work done on this family of stoic rodents just goes to show that “pain, while important, can still be very fluid,” says Simmie Foster, a neuroscientist and pain expert at Harvard Medical School and Boston Children’s Hospital who was not involved in the study. “Pain responds to a changing environment...and there are instances in which it’s beneficial to adapt.”

Given what these critters have to deal with on a daily basis, pain tolerance might just be another notch in the mole-rat superpower belt. After all, it’s in the harshest environments that the most creative solutions for survival often arise. “[These rodents] have been forced to defy dogmas and figure out how to live in these circumstances,” Buffenstein says. “They don’t read the textbooks on how a mammals should behave...they’ve figured out their own best way.”

Naked or not, mole-rats can clearly take the heat.

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