The naked mole-rat—unsightly in appearance, unconventional in its habitat and unusual in how its body functions —doesn’t feel certain types of pain. As a result, this creature has been a valuable tool for researchers to learn more about the fundamental workings of the pain system. In the long run, this may improve the understanding of chronic pain in people and advance the search for new pain relievers.
A recent study builds upon past research by examining nine African rodent species related to the naked mole-rat, with diverse habitats ranging from the Horn of Africa to the highveld of South Africa.
An international collaboration led by Gary Lewin, Max Delbrück Center for Molecular Medicine, Berlin, Germany, working with African researchers at the University of Pretoria, Republic of South Africa, and scientists in Morogoro and Dar es Salaam, Tanzania, identifies four more instances of pain insensitivity, along with some new clues to the underlying causes.
The investigators discovered that, apart from the naked mole-rat, three of the species were insensitive to pain caused by capsaicin (the component of chili peppers that makes them hot) and low pH (acid).
Another species, the highveld mole-rat, was completely insensitive to a substance called allyl isothiocyanate (AITC), which is responsible for giving mustard and wasabi their pungent taste. Normally, capsaicin, acid and AITC cause strong pain responses in animals.
“By studying diverse species that have evolved in different environments, one can learn about adaptations in pain processing to these environments and hypothesize about why certain species evolve resistance to different noxious chemicals,” said Ewan St. John Smith, University of Cambridge, UK, who studies the pain system in naked mole rats but was not involved in the new research.
“This study nicely demonstrates what’s there to be found if you look for it, and in the same way that we can understand more about pain by studying rare genetic variations in humans, we can also discover a lot by understanding the basis of unusual pain behaviors in animals,” Smith continued.
The findings were published May 31st in the journal Science.
Standing out from the crowd
The naked mole-rat’s habitat of crowded underground burrows, where hundreds of animals produce high levels of carbon dioxide (CO2), would normally be toxic to other rodents. The high levels of CO2 produce an acidic environment in the mole-rats’ bodies, which should be painful. However, this isn’t the case in naked mole-rats, and the crowded burrows could explain why this species evolved insensitivity to pain from acid.
To see if other mole-rat species have similar insensitivities to pain based on their habitat, co-first authors Ole Eigenbrod and Karlien Debus along with colleagues began by exposing the different species to each of three painful substances: capsaicin, hydrochloric acid (HCl) or AITC. They then examined pain behaviors such as paw licking or flinching in response to these substances.
They discovered that two of the species completely lacked a pain response to some of the substances. In particular, the Natal mole-rat was insensitive to capsaicin, and both the Cape mole-rat and East African root-rat were insensitive to HCl.
Why so (in)sensitive?
Eigenbrod then looked closely at each of the species’ genetic makeup to see if there were any changes that might explain these observations. They found that all species had broadly similar levels of pain-sensing neurons and ion channels responsible for pain processing. Ion channels are proteins important for the electrical signaling of neurons.
This suggested that the lack of a pain response to capsaicin seen in the Natal mole-rat was not because of the absence of neurons or ion channels that are activated by this painful substance.
Previous studies from Lewin showed that in naked mole rats, there was an unusual pattern of connections involving neurons in the spinal cord that respond to capsaicin. That helped explain the insensitivity to capsaicin in naked mole rats, but whether that also accounts for the Natal mole-rat’s pain insensitivity to capsaicin is unclear, Lewin said.
All three species insensitive to acid (the naked mole-rat, Cape mole-rat and East African root-rat) showed reduced amounts of two ion channels known to contribute to acid insensitivity.
However, as St. John Smith points out, these ion channel changes likely don’t fully explain why the animals don’t feel pain caused by acid.
“We have to bear in mind that acid, unlike capsaicin, modulates so many different ion channels and receptors [a type of protein on the surface of cells], making it pretty complicated to work out exactly what is going on.”
There’s a leak somewhere
To date, researchers thought that AITC caused pain in all animals. However, remarkably, in the new study, the highveld mole-rat displayed a complete lack of sensitivity to this substance; mustard or wasabi would have little sway in these creatures, if they were ever to encounter it!
The ion channel responsible for sensing AITC and causing the painful response to it is called TRPA1. The researchers were interested to see if this channel was working properly in the animals who didn’t respond to AITC.
So, they grew cells that contained the TRPA1 ion channel from highveld mole-rats in a petri dish. They discovered that the amount of AITC needed to activate the channel was 10-times higher than that required when using AITC to activate TRPA1 from mice. This could help to explain why the highveld mole-rats don’t feel pain from AITC.
The researchers then discovered that, compared to all the other species, the highveld mole-rat had higher levels of an ion channel called NALCN, a so-called sodium leak channel (NALCN). In most circumstances, sodium channels allow ions (positively or negatively charged molecules) into neurons to enable the cells to “fire” and send electrical signals from the site of an injury to the brain. But NALCN helps dampen down those signals. Further experiments would show that the increased amount of NALCN was responsible for the lack of response to AITC in the Highveld mole-rats.
Habitats hold the answer
So why is the highveld mole-rat insensitive to AITC?
The answer came from some careful observation of its habitat. One of the team members, Daniel Hart, University of Pretoria, Republic of South Africa, noticed that, in the wild, highveld mole-rats share their burrows with Natal drop tail ants, a particularly aggressive species that bite invaders.
Hart gathered some of these ants and injected their venom into several species of mole-rats that have different habitats compared to the highveld mole-rat. The venom produced strong pain responses in all species, similar to what happens after exposure to AITC. But the venom had no impact on pain behaviors in the highveld mole-rats. This showed why they are not bothered by sharing a habitat with these aggressive ants.
The new research shows the value of studying unusual animals, their environments and their responses to painful substances. By understanding how evolution has made some species insensitive to certain types of pain, researchers can take that information to learn more about when the pain system goes awry in the opposite direction, as in the case of chronic pain. That could one day even lead to better drugs to treat pain in people.
This story is a plain language translation of a story that first appeared on the IASP Pain Research Forum.
Dara Bree is a postdoctoral research fellow at Beth Israel Deaconess Medical Center and Harvard Medical School.