Imagine the sting of entering a hot tub with a bad sunburn. The
naked mole rat wouldn't be bothered, but most animals would sense this
as thermal hyperalgesia. and the scientists who conducted the study have
a good idea of what goes on at a cellular level when this happens.
Now, new research has pinpointed the evolutionary change that made
the naked mole rat so uniquely pain-free, suggested a study published in Cell Reports
‘The evolutionary change that made the naked mole rat so uniquely pain-free has been demonstrated by a study published in Cell Reports.’
The African naked mole rat is an odd, homely creature with the
closest thing to real-life super powers on earth. These small rodents
can live for 32 years, they are cancer-resistant, and they are
impervious to some types of pain.
"We think evolution has selected for this tweak just subtly enough
so that the pain signaling becomes non-functional, but not strong enough
that it becomes a danger for the animal," says lead author Gary R.
Lewin, a professor at the Max-Delbruck Center for Molecular Medicine in
The scientists who conducted the study have
a good idea of what goes on at a cellular level when the naked mole rat is exposed to thermal hyperalgesia.
In response to high temperatures and inflammation around sensory
neurons, nerve growth factor (NGF) molecules bind to a receptor called
TrkA. This kicks off a cascade of chemical signals that "sensitize" an
ion channel - called TRPV1 - on the surface of the sensory neuron so
that it opens. Once TRPV1 opens, it results in sensory nerve firing that
tells the brain to register pain at temperatures that are not normally
Through more than a dozen carefully designed experiments, Lewin and
colleagues found what differentiates the naked mole rat from other
animals in this process - a small change in their TrkA receptor.
For example, if the scientists swapped out the TRPV1 channels in a
mouse cell for naked mole rat versions of TRPV1, then thermal
hyperalgesia occurred normally. But if a cell had a common rat TRPV1 and
a naked mole rat TrkA, then the cell couldn't sense thermal
Researchers compared the gene for the naked mole rat's TrkA receptor
to those of 26 other mammals, and five other African mole rat species.
They discovered a switch of just one to three amino acid changes on one
section of the naked mole rat TrkA receptor that make it less sensitive.
"Even though the naked mole rat's version of the TrkA receptor is
almost identical to that of a mouse or a rat, it has a very significant
effect on the animal's ability to feel pain," says Lewin.
Further experiments revealed that the tweak on the naked mole rat's
TrkA receptor didn't render it dysfunctional, but hypo-functional. Their
TrkA receptor could respond like that of other animals, if the naked
mole rat cell was exposed to ten times the normal concentration of NGF.
This subtle difference between a hypo-functional and a dysfunctional
TrkA receptor may explain why the naked mole rat could survive without
the typical neurodegeneration found in animals with mutations that
completely shut down NGF signaling. Previous research has shown
developing embryos require NGF signaling to develop a normal pain
However, the new study found that naked mole rats are born with
roughly the same number of pain sensors as newborn mice. It's only by
adulthood that the naked mole rat's pain sensors dwindle by two-thirds
compared to any other mammal. Evolution may have selected a TrkA
receptor that works well enough for the animal developing as an embryo,
but leaves adults with fewer nerve receptors and partially pain-free.
Losing thermal hyperalgesia might help the naked mole rats survive
in their crowded underground colonies, where the close contact can be
uncomfortably hot but thermal hyperalgesia may not be helpful in this
warm environment. And it's possible that losing sensory neurons as
adults may help the animals conserve energy.
"They live in desert regions underground, and they have to do a lot
of work to get their food," says Lewin. "They have the lowest metabolic
rate of any mammal. Evolution has shut down everything that is not
absolutely necessary - including extra nerve receptors."
Lewin and his colleagues are planning future studies in mice bred to have the unique naked mole rat TrkA receptor.
"We hope to see that these modified mice will show lots of features that make naked mole rats unique," says Lewin.