Social influences can profoundly modulate pain in both humans and rodents. A handful of studies have shown that when two animals experience the same pain stimulus while housed together, exposure to one another causes each animal to have a greater pain response than if they were housed alone. Now, new research shows that not only can social factors enhance pain in the setting of injury or noxious stimulation, but they can also cause pain in control mice—and without the need for the animals to ever interact.
Using three mouse models of hyperalgesia (complete Freund’s adjuvant (CFA) injection, morphine withdrawal, and alcohol withdrawal), a team of researchers led by Andrey Ryabinin, Oregon Health and Science University School of Medicine, Portland, US, demonstrates that the induction of pain in one set of mice also caused pain in a separate set of control mice—controls that were housed in the same room, in different cages, and were not exposed to a painful stimulus. This effect could be measured with mechanical, thermal, and chemical pain behavioral assays. The investigators further show that olfactory cues were responsible for the transfer of alcohol withdrawal-induced hyperalgesia.
“It’s a very interesting finding—and puzzling,” says Jeffrey Mogil, McGill University, Montreal, Canada, who was not involved in the study. “In previous studies, there had to be a pain stimulus. Here, the controls are having apparent pain hypersensitivity without ever having the stimulus in the first place, which is surprising,” continued Mogil.
The new study was published online October 19 in Science Advances.
That social interactions can modulate the experience of pain is not a new idea (Goubert et al., 2005). This has been thought of as “emotional contagion,” a form of empathy, where pain-related behaviors in one rodent directly enhance similar pain-related behaviors in another rodent when they interact with one another (Langford et al., 2006; Martin et al., 2015).
In earlier research, rats genetically predisposed to have lower pain phenotypes experienced enhanced pain behaviors following nerve injury if housed in the same cage as rats that were predisposed to have higher pain phenotypes (Raber and Devor, 2002). Similarly, mice living in the same cage had enhanced writhing behavior during the acetic acid test if they could see one another in pain (Langford et al., 2006). In a more recent investigation, naive mice housed with cagemates who had undergone sciatic nerve lesion also experienced greater pain behaviors during the acetic acid test, which the authors hypothesized was due to the stress of living with a conspecific in pain (Baptista-de-Souza et al., 2015). It’s clear, then, that social influences can modulate pain behavior, but it was unknown whether those influences also apply to animals not subjected to pain and living apart (so-called “bystander” animals), and if so, whether visual or auditory cues were necessary for that effect.
Controls feel pain, too
Ryabinin and colleagues initially set out to explore whether alcohol withdrawal caused pain in mice, as is seen in humans. In an experimental group, mice had free access to ethanol for six days, followed by a 24-hour withdrawal period without alcohol. Control mice were housed without alcohol in the same room, but in different cages. Both groups were then tested for mechanical sensitivity with Von Frey hairs (VFHs).
“We found that alcohol withdrawal indeed led to sensitivity in the experimental mice, but surprisingly, it also did in the controls,” Ryabinin said, but it was unclear why.
Monique Smith, the first author of the study and now at Stanford University, US, discussed the findings with Mary Heinricher, a pain researcher and study co-author at Oregon Health and Science University School of Medicine. “During my consultations with Mary, she agreed that it was possible for the animals to be communicating their pain, although we were all very surprised and somewhat skeptical,” said Smith.
To address this, Smith introduced a second no-alcohol control group, but one that was housed in an entirely separate room away from the first two groups. These animals continued to be pain-free.
The control animals in the same room as the experimental animals not only showed increased mechanical hyperalgesia, but also elevated chemical and thermal hyperalgesia, as measured with the formalin and hot water tail immersion tests, respectively. Similar results were also seen using CFA and morphine withdrawal models. Somehow, housing the animals that were in pain in the same room but different cages as the controls made the controls act as if they, too, were in pain.
A role for olfactory cues
Since the animals were housed individually and couldn’t see each other, the researchers wondered what other types of sensory modalities might account for the transfer of pain, hypothesizing that olfactory cues might play a role. To test this idea, Smith scooped up a small amount of dirty bedding from the alcohol withdrawal mice and placed it in an empty cage next to the cage of control mice that were in a separate room, the only group that previously did not experience pain. Even without having direct contact with this dirty bedding, these mice developed mechanical and chemical hypersensitivity within 24 hours, as measured with VFHs and the formalin test, respectively.
Smith wondered if this transfer of pain might be due to stress, but found no differences between any of the groups in plasma cortisol levels, nor in behavior on the elevated plus maze, two measures of stress. “There is something in the bedding, but we really don’t know what it is,” Ryabinin said.
The study provides further evidence that the social aspect of the biopsychosocial model of health affects pain, even in rodents. Basic scientists using animals may need to consider how this will influence their studies.
“The big message here to researchers using animals is to reconsider your housing conditions,” said Ryabinin.
Realistically, however, the practicality of housing animals in entirely separate rooms may be challenging. “[Doing so may] be even worse because there might be differences in the stress or noise conditions between the rooms,” Mogil said.
The results may prove valuable for researchers interested in using rodents to study the more common scenario seen in humans, where someone in chronic pain may live with others who are not. “People living with chronic pain patients are definitely influenced by them. Now we have a model where we can test that social influence without the requirement of an injury in both groups and try to use the findings to better understand what may happen in humans,” said Ryabinin.
Given the olfactory component, one may go so far as to say that pain could be considered contagious. “This paper suggests that it might be true, but obviously we want to treat this suggestion with a lot of healthy skepticism. For one thing, humans are not nearly as olfactory as mice,” Mogil explained.
Nathan Fried is a postdoctoral fellow at the University of Pennsylvania, Philadelphia, US.
Image credit: anyaivanova/123RF Stock Photo
Correction: The original sentence descrbing the results from Raber and Devor included the phrase “that also underwent nerve injury” at the end of the sentence. In the corrected version, that phrase has been deleted, in order to clarify that the effect of housing with animals predisposed to have higher pain phenotypes did not rely on these animals undergoing surgery. That is, housing low-pain phenotype animals that underwent surgery with high-pain phenotype animals that did not undergo surgery was sufficient to enhance the pain state of the low-pain phenotype animals.