To most people, the phrase “I feel your pain” is just an expression of sympathy. But it’s also a real biological phenomenon, a new study in rodents suggests. Healthy mice living in the same room with mice experiencing pain are up to 68% more sensitive to pain themselves, regardless of their stress levels, according to the new study, which found that mice could scent when their fellows were suffering. The discovery suggests that current methods for studying rodent pain may need to be overhauled, and it may even point to a novel mechanism for pain transmission between humans, the authors say.
Andrey Ryabinin, a behavioral neuroscientist at Oregon Health & Science University in Portland, and colleagues stumbled on the phenomenon largely by accident. They were studying the effects of alcohol withdrawal in mice, looking for new ways to help people overcome addiction. One of the most common, but challenging, symptoms of alcohol withdrawal is an intense, generalized pain throughout the body—a difficult-to-define condition that often leads people back to drinking, he says. Recreating those painful withdrawal symptoms in mice is difficult, leading some researchers to question whether the rodents are a good model for alcohol addiction.
Ryabinin and his team were using a standard setup: The mice are allowed to lap freely at an ethanol and water solution, but then go into withdrawal after the bottle is removed. A control group, housed in the same room, drinks only water. Using multiple measures of pain sensitivity—including brushing their forepaws with a thin hair and dipping their tails into hot water, the researchers attempted to gauge how withdrawal might be affecting the addicted rodents.
The initial results were disappointing, showing no significant difference between the two groups. Before giving up, however, the scientists decided to cage the control mice in a different room. This time, the sober controls showed far less pain sensitivity than the controls in the previous experiment, suggesting that the latter group had somehow acquired a heightened pain sensitivity from their roommates, Ryabinin says.
To test that idea, Ryabinin and colleagues repeated the original experiment using two additional forms of painful stimuli—injecting an immune molecule that causes inflammation into one of the rodents’ paws, and forcing them into withdrawal from morphine. Control mice housed in the same room had up to a 68% higher pain sensitivity than those in a different room, the group reports today in Science Advances. To rule out the possibility that they were measuring only the animals’ anxiety, and not pain sensitivity, the team put the mice through standard stress tests, in which they allowed the rodents to explore an elevated, exposed platform before measuring the levels of stress hormones in their blood. Their conclusion: Stress did not play an important role in the transmission of pain from animal to animal, because the mice housed with their suffering fellows explored the platform as readily as mice housed without neighbors in pain, and there was no significant difference in hormone levels. That was surprising, Ryabinin says: “Frankly, we thought that it was the transfer of stress or arousal” that had caused the effect.
Previous studies suggest that mice can sense one another’s pain simply by looking at each other, but the mice housed in the same room were not close enough to give them a full view, Ryabinin says. He wondered whether scent might be responsible instead. So the team removed bedding from the cages of mice that were in pain, and put it in the cages of the control mice in a different room. Soon, isolated mice showed sign of heightened pain sensitivity, suggesting that smell was likely the messenger.
This is the first time scientists have shown that pain in one colony of mice can affect an entirely separate colony, even when they are out of sight, says Loren Martin, a behavioral neuroscientist at the University of Toronto in Canada. Although he finds it surprising that such a large effect would have gone unnoticed in previous experiments, the findings are “pretty exhaustive,” and “should be taken seriously” given that many pain studies house both treatment and control mice in the same room or cage, he says.
It’s too early to translate these findings to humans, but there is growing evidence that people also share their pain. For example, the spouses of people experiencing chronic pain often have an increased pain sensitivity, Ryabinin says. Although those results could potentially be explained by high stress levels among caregivers, “now we’ve found another route for how this could be explained,” he says.