How the naked mole-rat escapes inflammatory pain

In injuries and inflammation, naked mole-rats do not develop normal hypersensitivity to temperature stimuli. This is due to a tiny change in a receptor molecule on cells called TrkA, as a research team from the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) and Excellence Cluster NeuroCure has now discovered. The work, which appears in the journal Cell Reports, may be important for pain therapy in humans.

When an animal suffers an injury or inflammation, nearby tissue usually becomes highly sensitive to pain. Skin becomes red and puffy, for example, and is hypersensitive to heat. This condition, called “thermal hyperalgesia,” acts as a warning that helps animals avoid further injuries.

The only known animals unable to feel thermal hyperalgesia are naked mole-rats, rodents which live in extremely harsh conditions in underground tunnels. MDC researchers Dr. Damir Omerbašić and Dr. Ewan St. J. Smith from Prof. Gary Lewin’s lab have now found out the reasons and presented their work in the latest issue of the journal Cell Reports.

Hyperalgesia is mediated by the signaling molecule Nerve Growth Factor (NGF), which is also responsible for the growth of new nerves, especially during embryonic development. Hyperalgesia occurs when inflamed or injured tissue releases NGF molecules which subsequently bind to protein molecules on the surfaces of specialized, pain-sensing nerve cells. These surface proteins are called TrkA receptors, and when they are stimulated by NGF they relay a signal into the nerve cell. This causes other proteins to interact with the receptor, starting a cascade of biochemical signals which ultimately makes the cell oversensitive to thermal stimuli.

A small change in the TrkA receptor has a big effect

TrkA receptors evolved in an ancient animal and have been passed down to all its descendants. TrkA is so important that it has been protected from most evolutionary change.

When the researchers compared the receptor of naked mole-rats to TrkA receptors in other mammals, they found minute differences in a region of the molecule that projects into the cell interior. This region triggers the biochemical signaling cascade and is virtually identical in all mammals.

In naked mole-rats, the differences in this portion of the receptor alter a few of the protein’s building blocks and severely diminish the signal-relaying action of the TrkA receptor. The researchers found that it took ten times the amount of NGF compared to TrkA receptors from other animals to trigger the signaling cascade, explaining why naked mole-rats are almost completely insensitive to thermal hyperalgesia.

An evolutionary sweet spot?

NGF has another important function: it stimulates the growth and maintenance of nerves as the nervous system develops in the embryo. That’s why defects of the TrkA receptor in other mammals often lead to a degeneration of the nervous system during embryonic development. “The nervous system of the naked mole-rat can develop normally because while the function of its TrkA receptors is lowered, it is not completely abolished,” principal investigator Gary Lewin explains. “Evolution has selected a version of the molecule that can send just enough signal to build a proper nervous system, but not enough to make cells hypersensitive to pain.”

The difference surely makes life more bearable for the rodents, which live underground in densely packed colonies. Injuries and inflammations are common, and under the same conditions other mammals would suffer intense, continual pain.

That’s a daily experience for many people who suffer from chronic pain. In many cases the problem also involves NGF and TrkA; treatments that block the binding of these two molecules have had very positive effects in clinical trials. It’s another example, Lewin says, of how basic research – even when it starts in a very unusual animal – could pave the way toward new human therapies.