Without pain, thanks to evolution – ScienceDaily

About ten years ago, the naked mole rats of the Max Delbrück Molecular Medicine Center (MDC) became famous almost overnight. This is thanks to the work of Gary Lewin of Berlin and Thomas Park of Chicago, who studied together the strange sensory world of the naked mole rat. Park and Lewin have shown that these African terrier rodents are remarkably resistant to pain. In a 2008 article in the newspaper PLOS Biology, they reported that mole rats did not experience any pain when exposed to acid or capsaicin – the substance that gives heat to peppers. The experiments on mole rats have attracted worldwide attention.

For this latest study, has just appeared in ScienceLewin teamed up with colleagues from South Africa and Tanzania to test more cases of insensitivity to pain. "The knowledge provided by our studies on these animals should, among other things, contribute to the development of new analgesic drugs," said Lewin, who leads the molecular physiology group of somatic sensation at the MDC.

Working closely with a global expert in mole rat biology, Nigel Bennett of the University of Pretoria in South Africa, Gary Lewin, Thomas Park and his colleagues explored how naked mole rats and eight other related species react to three burning substances on the skin of humans and other mammals. These substances were: dilute hydrochloric acid, capsaicin and allyl isothiocyanate (AITC). The AITC is what gives wasabi, the popular condiment served with sushi, its extremely pungent taste. The idea was that mole rats are naturally exposed to these substances and other similar substances in nature.

Only the high-level mole rat is insensitive to wasabi sting

in the Science article, whose main authors are Ole Eigenbrod and Karlien Debus, scientists report that three species of mole rats have proved insensitive to acid. Interestingly, these three species are not closely related to the course of evolution. Two species did not show signs of pain after receiving a solution of capsaicin injected into their paws. "Other people have briefly raised their legs or licked, which shows us that these animals actually felt a brief sensation of pain," Lewin explains.

Only one mole-tailed species has been found to be impervious to AITC. It was not the naked mole rat, but another burrowing rodent called the highveld mole rat, which takes its name from the eastern region of South Africa where the animals are exclusively found. "It was a thrilling discovery for us," says Lewin. "AITC attacks amino acids in the body and can therefore destroy proteins, which is why all the other species we know avoid coming into contact with the substance." The high-level mole rat was the only species of the experiment to have no problem with TIAC.

Everything is due to modified ion channels

In order to discover the molecular reasons for the remarkable pain resistance of the mole rat, the researchers collected sensory tissue from the spinal cord and dorsal root ganglia of the nine species studied. In the dorsal root ganglia, there are clusters of neurons that transmit pain signals to the spinal cord. "Thanks to advanced sequencing technology, we have been able to compare the activity of about 7,000 genes within this tissue," reports Lewin.

Quite quickly, the team observed that the activity of two genes was impaired in animals that felt no pain. These genes contain the blueprint for the TRPA1 and NaV1.7 ion channels. We already know that these two channels are involved in the perception of pain.

"The AITC and many other irritants present in the roots – one of the main food sources of the mole rat – activate TRPA1," Lewin explains. This is why, during the course of evolution, many species have downregulated the gene of this channel. "But the" wasabi chain "is the only one to be completely extinguished in the Highveld wireworm," says Lewin. He and his team then discovered that this was due to a particularly active gene in another channel – the constitutively open NALCN channel, known as the "leak channel". The research group found that the expression of this channel was the only one to have been significantly modified in the highveld mole rat.

Pain resistance in the mole rat can be turned off

Lewin was particularly surprised by the results of a new experiment. "When we blocked the NALCN channel by administering a drug that blocked it, the highveld mole rat suddenly became susceptible to AITC," he says. But just one day after the administration of the antagonist, the animals regained their indifference to the substance. "Of the thousands of genes we examined, we had obviously found the gene responsible for the remarkable pain resistance of the highveld mole rat," says Lewin with a smile, delighted that luck was also clearly his side.

Daniel Hart, a PhD student working with Nigel Bennett, discovered that high-level mole rats often share their burrows with Myrmicaria natalensis, better known as the Natal droptail. "These insects are known for their aggressive nature and their very pungent venom," Lewin said. When this ant venom was injected into their paw, all the mole-rat species participating in the study experienced a brief moment of pain, with the exception of the highveld mole rat. But when researchers blocked the NALCN channel in the high-level mole rat, these animals became susceptible to venom.

New discoveries could help pharmaceutical research

Lewin assumes that "throughout the evolution, the highveld mole rat clearly acquired a highly active gene for a single ion channel, which allowed it to settle in places that are avoided by of other species of mole-rats ". The MDC scientist sees this as another wonderful example of how the environment shapes long-term evolution. "From a more practical point of view, this discovery could well lead to the development of extremely effective painkillers," he adds. "The high-level mole rat has shown us that high expression of the NALCN channel appears to be a very effective way of relieving pain."