Picturing pain could help unlock its mysteries and lead to better treatments

Understanding the science behind pain, from a simple “ouch” to the chronic and excruciating, has been an elusive goal for centuries. But now, researchers are reporting a promising step toward studying pain in action. In a study published in the Journal of the American Chemical Society, scientists describe the development of a new technique, which they tested in rats, that could result in better ways to relieve pain and monitor healing.

Sandip Biswal, Frederick T. Chin, Justin Du Bois and colleagues note that current ways to diagnose pain basically involve asking the patient if something hurts. These subjective approaches are fraught with bias and can lead doctors in the wrong direction if a patient doesn’t want to talk about the pain or can’t communicate well. It can also be difficult to tell how well a treatment is really working. No existing method can measure pain intensity objectively or help physicians pinpoint the exact location of the pain. Past research has shown an association between pain and a certain kind of protein, called a sodium channel, that helps nerve cells transmit pain and other sensations to the brain. Certain forms of this channel are overproduced at the site of an injury, so the team set out to develop an imaging method to visualize high concentrations of this protein.

They turned to a small molecule called saxitoxin, produced naturally by certain types of microscopic marine creatures, and attached a signal to it so they could trace it by PET imaging. PET scanners are used in hospitals to diagnose diseases and injuries. When the researchers injected the molecule into rats, often a stand-in for humans in lab tests, they saw that the molecule accumulated where the rats had nerve damage. The rats didn’t show signs of toxic side effects. The work is one of the first attempts to mark these sodium channels in a living animal, they say.

Grasshopper Mice Are Numb to the Pain of the Bark Scorpion Sting

The painful, potentially deadly stings of bark scorpions are nothing more than a slight nuisance to grasshopper mice, which voraciously kill and consume their prey with ease. When stung, the mice briefly lick their paws and move in again for the kill.

The grasshopper mice are essentially numb to the pain, scientists have found, because the scorpion toxin acts as an analgesic rather than a pain stimulant.

The scientists published their research this week in Science.

Ashlee Rowe, lead author of the paper, previously discovered that grasshopper mice, which are native to the southwestern United States, are generally resistant to the bark scorpion toxin, which can kill other animals.

It is still unknown why the toxin is not lethal to the mice.

“This venom kills other mammals of similar size,” said Rowe, Michigan State University assistant professor of neuroscience and zoology. “The grasshopper mouse has developed the evolutionary equivalent of martial arts to use the scorpions’ greatest strength against them.”

Rowe, who conducted the research while at The University of Texas at Austin, and her colleagues ventured into the desert and collected scorpions and mice for their experiments.

To test whether the grasshopper mice felt pain from the toxin, the scientists injected small amounts of scorpion venom or nontoxic saline solution in the mice’s paws. Surprisingly, the mice licked their paws (a typical toxin response) much less when injected with the scorpion toxin than when injected with a nontoxic saline solution.

“This seemed completely ridiculous,” said Harold Zakon, professor of neuroscience at The University of Texas at Austin. “One would think that the venom would at least cause a little more pain than the saline solution. This would mean that perhaps the toxin plays a role as an analgesic. This seemed very far out, but we wanted to test it anyway.”

Rowe and Zakon discovered that the bark scorpion toxin acts as an analgesic by binding to sodium channels in the mouse pain neurons, and this blocks the neuron from firing a pain signal to the brain.

Pain neurons have a couple of different sodium channels, called 1.7 and 1.8, and research has shown that when toxins bind to 1.7 channels, the channels open, sodium flows in and the pain neuron fires.

By sequencing the genes for both the 1.7 and 1.8 sodium channels, the scientists discovered that channel 1.8 in the grasshopper mice has amino acids different from mammals that are sensitive to bark scorpion stings, such as house mice, rats and humans. They then found that the scorpion toxin binds to one of these amino acids to block the activation of channel 1.8 and thus inhibit the pain response.

“Incredibly, there is one amino acid substitution that can totally alter the behavior of the toxin and block the channel,” said Zakon.

The riddle hasn’t been completely solved just yet, though, Rowe said.

“We know the region of the channel where this is taking place and the amino acids involved,” she said. “But there’s something else that’s playing a role, and that’s what I’m focusing on next.”

Some resistance to prey toxins in mammals has been found in other species. The mongoose, for example, is resistant to the cobra. And naked mole rats’ eyes do not burn in pain when carbon dioxide builds up in their underground tunnels.

This study, however, is the first to find that an amino acid substitution in sodium channel 1.8 can have an analgesic effect.

Rowe said studies such as this could someday help researchers target these sodium channels for the development of analgesic medications for humans.

Researchers make exciting discoveries in non-excitable cells

It has been 60 years since scientists discovered that sodium channels create the electrical impulses crucial to the function of nerve, brain, and heart cells — all of which are termed “excitable.” Now researchers at Yale and elsewhere are discovering that sodium channels also play key roles in so-called non-excitable cells.

In the Oct. 16 issue of the journal Neuron, Yale neuroscientists Stephen Waxman and Joel Black review nearly a quarter-century of research that shows sodium channels in cells that do not transmit electrical impulses may nonetheless play a role in immune system function, migration of cells, neurodegenerative disease, and cancer.

“This insight has opened up new avenues of research in a variety of pathologies,” Waxman said.  

For instance, Waxman’s lab has begun to study the functional role of voltage-gated sodium channels in non-excitable glial cells within the spinal cord and brain. They are currently investigating whether sodium channels in these non-excitable cells may participate in the formation of glial scars, thereby inhibiting regeneration of nerve cells after traumatic injury to the spinal cord or brain.

In a world of chronic pain, individual treatment possible

An investigation into the molecular causes of a debilitating condition known as “Man on Fire Syndrome” has led Yale researchers to develop a strategy that may lead to personalized pain therapy and predict which chronic pain patients will respond to treatment.

More than a quarter of Americans suffer from chronic pain and nearly 40 percent do not get effective relief from existing drugs. In many common conditions such as diabetic neuropathy, no clear source of pain is found.

The new study published in the Nov. 13 issue of Nature Communications used sophisticated atomic modeling techniques to search for mutations found in a rare, agonizing, and previously untreatable form of chronic pain called erythromelagia, commonly referred to as “Man on Fire Syndrome.” Researchers discovered that one of those mutations seem to predicted whether a patient would respond positively to drug treatment.

“Hopefully we can use this knowledge to help chronic pain patients in more systematic ways, and not depend upon trial and error,” said Yang Yang, postdoctoral research associate in the Department of Neurology and lead author of the paper.