Pain Insensitivity in Mole-Rats, and How It Could Help Us

Naked mole-rats and their kin are resistant to certain types of pain.

Posted Apr 22, 2020

John Brighenti, via Flickr. Distributed under a CC BY 2.0 license.
Naked mole-rat.
Source: John Brighenti, via Flickr. Distributed under a CC BY 2.0 license.

Naked mole-rats are weird. Native to East Africa, they live underground in highly ordered and hierarchical colonies with a single breeding queen, more like ants or termites than mammals. Some of their most striking physiological adaptations include an extraordinarily long lifespan (30+ years), apparent resistance to cancer, and resistance to extremely low levels of oxygen and high levels of carbon dioxide.

But it turns out naked mole-rats are not completely alone; they come from a family of weirdos. In a recent review paper, Gary Lewin of the Max Delbrück Center for Molecular Medicine, Thomas Park of the University of Illinois at Chicago, and Ewan St. John Smith of the University of Cambridge describe what we know about pain insensitivity in naked mole-rats and some of their close relatives.

Naked and Unafraid

“In the popular literature, it’s often said that naked mole-rats are ‘pain-free’ and that’s not really the case,” says Lewin. “They just have certain types of pain that are either missing or reduced.”

In 2008, Lewin and Park reported that naked mole-rats do not feel the burn of chili peppers’ active ingredient, capsaicin, nor the sting of acid. Additionally, naked mole-rats do not show hypersensitivity to a variety of inflammatory and chemical stimuli (hypersensitivity is a pain response to stimuli that are not normally painful; think about how a hot shower feels when you have a sunburn!).

Lewin and his colleagues dug deeper to figure out the molecular changes that happened in naked mole-rats to make them insensitive to these kinds of pain.

In mice and other mammals, capsaicin activates an ion channel expressed by pain receptors called TRPV1. Lewin and his colleagues say altered connectivity of TRPV1-positive pain receptors could explain the lack of pain response in naked mole-rats.

In the case of acid, a voltage-gated sodium channel called NaV1.7 is also involved. Naked mole-rats possess a genetic mutation in this channel that prevents neurons from firing in response to acid; hence, no pain response.

Hypersensitivity after exposure to painful stimuli is dependent on the release of a peptide called nerve growth factor. But if you inject nerve growth factor in a naked mole-rat, it does not become hypersensitive. That’s because a few changes in the genetic code for the nerve growth factor receptor make it less efficient in naked mole-rats.

Nigel C. Bennett, via Wikimedia Commons. Distributed under a CC BY SA 3.0 license.
Cape mole-rat.
Source: Nigel C. Bennett, via Wikimedia Commons. Distributed under a CC BY SA 3.0 license.

As to the question of why naked mole-rats have lost these types of pain, Lewin says no one knows for sure but the adaptation is presumably advantageous. He and his colleagues believe one reasonable speculation is that acid insensitivity evolved in these animals in response to their living conditions. Naked mole-rats live in crowded, underground colonies that are low in oxygen and high in carbon dioxide, which can produce tissue acidosis in other animals. Acid insensitivity could help them live in such an environment.

No Pain, Net Gain

There are as many as 70 other species of African mole-rats. This diversity led Lewin and his colleagues to test whether pain insensitivity is unique to naked mole-rats or if it is a family affair.

The researchers tested nine species for their sensitivity to capsaicin, acid, and a compound called AITC (allyl isothiocyanate) – the active, pungent ingredient in mustard oil and wasabi. They found one additional mole-rat that was insensitive to capsaicin (the Natal mole-rat) and two more species insensitive to acid (the Cape mole-rat and the East African root rat).

Lewin and his colleagues used AITC as a control in their experiment. The molecular mechanism to detect such substances is so conserved in the animal kingdom, they expected all the mole-rats to find it unpleasant.

“All animals that have been tested avoid this substance, from primitive organisms like planaria to insects to fish to mammals,” says Lewin. “But one species, the Highveld mole-rat, surprised us. This animal does not respond to AITC.”

It’s the first case of complete insensitivity to AITC identified. The mechanism appears to be a new ion channel that is more highly expressed in the Highveld mole-rat than other animals and that shuts down the activation of pain receptors.

Dewald Kleynhans, University of Pretoria.
Highveld mole-rats often share their burrow systems with a native ant species, the Natal droptail ant.
Source: Dewald Kleynhans, University of Pretoria.

Lewin and his colleagues think they have found an answer to why the Highveld mole-rat has evolved this type of pain resistance. These mole-rats share their burrows with a highly aggressive stinging ant, the Natal droptail ant. When these ants bite, they inject a venom into the wound that causes a painful, stinging sensation.

Injection of the ant venom into a paw resulted in pain responses in every other mole-rat, even the naked mole-rat, but not in the Highveld mole-rat. Lewin and his colleagues found the ant venom activates the same receptor as AITC. He says the Highveld mole-rat likely evolved resistance to the venom of Natal droptail ants to live in regions avoided by other mole-rats.

“This is a trade-off the animals made; they got rid of a mechanism that other animals find essential to protect themselves, but it has given them an advantage where they can occupy a niche that other animals cannot,” says Lewin.

The Wisdom of Mole-Rats

This research, fascinating in its own right, also has practical applications. Even this small sampling of mole-rat species shows that several of these animals mastered the art of analgesia before humans ever evolved. The molecular mechanisms for shutting off pain discovered in mole-rats could lead to new ways to ameliorate pain in humans. Scientists are already studying nerve growth factor signaling and the sodium ion channel NaV1.7 as potential targets for new pain therapies, with promising results.

Lewin is continuing his investigations into some of the naked mole-rat’s other peculiarities. He’s especially interested in the extreme social lives of naked mole-rats. They live in colonies of up to 300 individuals with a queen who is the only breeding female. Their society is highly organized and hierarchical, with every animal having a rank and a job to do. Lewin is planning studies on the vocal communication of naked mole-rats, which he says have the most diverse vocal repertoire of any rodent known.

And still, Lewin says, that’s just the tip of the iceberg. “We haven’t even mentioned their longevity, cancer resistance, or metabolism,” he says. “A few years ago, we showed that naked mole-rats can go into a state of suspended animation for up to eighteen minutes without any oxygen and recover completely without any neurological or cardiac deficits whatsoever. So basically, they are resistant to stroke and cardiac arrest.”

For Lewin and his colleagues, this interface between evolutionary biology and biomedicine has been a fruitful area of research. “We see that the mole-rat can teach us how to accomplish things that are desirable for treating people or avoiding disease,” he says. “Evolution has had millions of years to come up with solutions. Now we have powerful scientific tools to study and understand these natural treasures.”

References

Smith, E.S.J., Park, T.J. & Lewin, G.R. Independent evolution of pain insensitivity in African mole-rats: origins and mechanisms. J Comp Physiol A (2020). DOI: 10.1007/s00359-020-01414-w.