The naked mole rat became an unlikely media star in 2008 when researchers showed it is highly resistant to certain types of pain. Physiologist Gary Lewin of the Max Delbrück Center for Molecular Medicine in Berlin, biologist Thomas Park of the University of Illinois at Chicago and their colleagues found that the odd-looking creatures are insensitive to acid and capsaicin, the substance that gives chilies their burn. Lewin’s team has now investigated a range of mole rat relatives, revealing that the naked variety is not the only one resistant to pain. The study uncovers a previously unknown trick for shutting down the sensation, which could lead to the development of new pain-relieving drugs.
The naked mole rat is the original mole rat species, from which numerous others evolved in various parts of Africa, Lewin says. This diversity across habitats makes mole rats an ideal group of animals to study. “As they populated Africa, they probably came into contact with all kinds of different environments,” Lewin says. “We wanted to know, ‘Are these special properties of the naked mole rat something all African mole rats have, or are they something to do with the environment they’re confronted with?’”
In a study published online Thursday in Science, the team assessed the responses of eight kinds of mole rats and two other rodent species to three substances that normally elicit pain: acid, capsaicin and allyl isothiocyanate (AITC), the substance that gives wasabi its fiery heat. When researchers injected the substances in one of the animals’ paws, those that experienced pain would lick or flick their limb. In addition to the naked mole rat, two other species (the Cape mole rat and East African root rat) were resistant to acid, and one other (the Natal mole rat) was resistant to capsaicin. The Highveld mole rat, named after the eastern South African region where it lives, was the only species impervious to AITC. “It’s absolutely remarkable that five of the [species studied] turned out to have evolved distinct sensory deficits,” says neurobiologist Jorg Grandl of Duke University, who was not involved in the study.
The researchers conducted a series of experiments in the Highveld mole rat to probe its resistance to AITC. Their findings revealed a previously unknown mechanism for suppressing pain, involving a single gene coding for an ion channel that, when highly active, prevents pain-sensing neurons from firing. This activity gives the animal a very specific resistance, presumably because it is restricted to cells that sense AITC. But researchers could target this channel in general, anywhere they find it, potentially opening up a whole new class of pain relievers. “Our findings could lead to a drug-discovery program to try and make molecules that increase the function of this channel,” Lewin says.
The researchers set out to dissect the genetic and molecular mechanisms underlying this striking variation. They took tissue samples from the spinal cords and dorsal root ganglia (bundles of spinal cord neurons that transmit pain information) of all the species and measured the activity of nearly 7,000 genes. The scientists found evidence of a normal complement of neurons for detecting painful stimuli in each species. And specialized proteins called ion channels, activated by capsaicin or AITC, were present at similar levels in all species—suggesting pain resistance is not simply a case of lacking the relevant detectors. There were differences, however. For instance, the three acid-resistant species had altered activity in 41 genes, almost all of which are likely expressed, or turned on, in sensory neurons, and a few of which are known to encode acid-sensing channels.
The team then focused on Highveld mole rats’ unique resistance. “This is the only animal that’s ever been found that doesn’t avoid AITC,” Lewin says. The channel activated by AITC is called TRPA1, and when the researchers examined the Trpa1 gene in Highveld mole rats, they found a mutation that reduces the channel’s sensitivity to the spicy chemical. But they also saw this mutation in three other species that do not have the Highveld mole rat’s immunity. Also, these rodents are not just resistant, they seem utterly impervious: increasing the concentration of AITC from 0.75 to 100 percent still failed to trouble the critters, which is difficult to explain purely in terms of reduced sensitivity. “In four different species, the channel had the same insensitivity, but only one species was completely behaviorally insensitive,” Lewin says. “So there had to be something else.”
The one gene whose activity was significantly different in Highveld mole rats codes for a channel called NALCN, which was more than six times as active as in other species. The team investigated NALCN’s function in laboratory-grown cells and found that it acts as a kind of “short circuit” that leaks current, preventing neurons from firing even when sensing the chemical that normally activates them. The researchers then injected Highveld mole rats with a drug that blocks NALCN, making them sensitive to AITC. The effect disappeared as the drug wore off, strongly supporting NALCN’s role in the species’ particular superpower. “The researchers used an impressive range of techniques, in multiple species, to look beyond variation in the genetic code and instead identify changes in levels of gene activity that appear critical for one species’ pain resistance,” says evolutionary biologist Kalina Davies of Queen Mary University of London, who was not involved in the study.
The researchers think these pain resistances are evolutionary adaptations. AITC and other irritants are present in roots, one of mole rats’ main food sources, so reduced sensitivity would be generally beneficial. Zoologist and team member Daniel Hart of the University of Pretoria in South Africa discovered that Highveld mole rats often share their burrows with an aggressive, venomous ant species, the Natal droptail. Experiments using venom from the ants showed that these mole rats were the only species resistant to it and that blocking NALCN abolished the resistance. “This is a fascinating dissection of the molecular machinery that senses noxious substances and how it evolved,” Grandl says.
The findings show that nature harbors more pain-perception mechanisms than previously appreciated. “The study suggests the response to noxious substances and the molecular basis controlling these are not as conserved as previously thought,” Davies says. “The results could have implications for our understanding of controlling pain.” Humans also possess the Nalcn gene so the implications for developing novel analgesics are fairly straightforward. “It’s the same gene we have, except it’s massively more expressed in the sensory neurons [of Highveld mole rats] than in any other species,” Lewin says. “It’s a standard procedure in the pharmaceutical industry to make a channel opener: a small molecule that would open the channel. And we’d predict that could have very powerful analgesic properties, because it would shut down pain receptors,” he explains. “With modern methods, we can really discover how evolution solved a problem.”