I Feel Your Pain – and Pain Relief, Too

The social transfer of pain and pain relief

A new study in mice identifies a unique brain circuit responsible for the social transfer of pain and pain relief. Image credit: Smith et al., Science. 2021 Jan 08; 371(6525):153-159.

Published March 3, 2021

Editor’s note: This story first appeared on the IASP Pain Research Forum and has been edited for RELIEF.

Empathy  the adoption of the emotional and sensory state of others is a fundamental social skill that helps people to better navigate the world around them. This phenomenon is not unique to people, as studies have shown that rodents can transfer feelings of fear, anxiety, and pain to others, too.

This raises a big question: What is happening in the nervous system that allows empathy, and the behaviors associated with empathy, to occur?

Now, new research from Robert Malenka, Stanford University, Palo Alto, US, and colleagues has identified a specific brain circuit involved in the social transfer of pain, as well as pain relief, from one mouse to another.

The researchers also show that this circuit, projecting from a brain region called the anterior cingulate cortex to another brain structure called the nucleus accumbens, is distinct from another circuit that facilitates the social transfer of fear.

Jeffrey Mogil, McGill University, Montreal, Canada, who first demonstrated social modulation of pain in mice back in 2006 but was not involved in the new study, said the research is “quite compelling.”

“The fact that one can define a neural circuit that is involved with this kind of social transfer, as opposed to pain perception itself, is very interesting – and something that many scientists would have doubted was possible not all that long ago,” said Mogil.

“The fact that these researchers demonstrated two different ways this can occur suggests that the scientific community may have underestimated the prevalence of it, and in doing so, downplayed the importance of the social aspect in the biopsychosocial model of pain,” Mogil continued, referring to the idea that biological, psychological, and social factors all contribute to the pain experience.

The study was published along with an accompanying Perspective article on January 8, 2021, in the journal Science.

A happy accident
Monique Smith, first author of the new study, said that she first discovered the social transfer of increased sensitivity to pain in animals “on accident.” This happened when she was a graduate student studying alcohol withdrawal in rodents.

“I was looking at pain as a measure of alcohol withdrawal and noticed that the water-drinking control mice were also hypersensitive to pain,” she said.

“At first, I thought I had made some kind of mistake and my control animals had somehow gotten the alcohol, too,” she continued. “But the more we looked into it, the more we realized that the withdrawn animal was actually transferring the pain behavior to other animals and we learned that a brain area called the anterior cingulate cortex plays an important role. It was all quite serendipitous.”

When Smith came to Malenka’s laboratory as a post-doctoral fellow, the two decided to work on experiments, using a variety of tools, to better understand how the brain gives rise to what Malenka described as a “primitive form of empathy.”

Transferring pain from one mouse to another
To begin, the researchers first developed a way to rapidly transfer pain to a “bystander” mouse housed with a cagemate. The cagemate received an injection, into a hind paw, of a substance that causes inflammation and pain in the paw.

Following just an hour of social interaction with the cagemate, the bystander mouse also had pain hypersensitivity, to both pressure and heat. This lasted for about four hours.

Next, looking at the activity of neurons in the bystander mice when the transfer of pain occurred, the researchers saw activity in brain regions like the anterior cingulate cortex (ACC) and nucleus accumbens (NAc). Previous research has shown that these are areas involved in empathy and social motivation.

Neurons in brain regions like the thalamus, amygdala and periacqueductal gray were also activated during the social transfer of pain. This, too, made sense since past research has revealed a role for these areas in the pain system.

Further experiments would reveal direct connections between neurons in the ACC and the NAc.

Let there be light
The team next turned to optogenetics, a method that uses light to turn the activity of neurons on or off.

When they used this approach to quiet the activity of neurons in the ACC, this stopped the social transfer of pain to the bystander animals. This implicated the ACC neurons as important players in that transfer.

Then, when the scientists activated the connections between the ACC and NAc, this prolonged the pain sensitivity in the bystander animals, for days. This was strong evidence of a role for the ACC-to-NAc circuit in the social transfer of pain.

What about fear?
The researchers were curious to learn whether the same brain circuit might regulate the social transfer of another emotion – fear, in this case.

For these experiments, bystander mice froze when they were able to observe another mouse receiving an electric shock to the foot; this freezing behavior is thought to indicate fear.

However, turning off the ACC-NAc circuit using optogenetics had no effect on the acquisition of this freezing behavior. It turned out that a different brain circuit, between the ACC and the amygdala, a brain region involved with emotions including fear, was responsible for the social transfer of fear.

The social transfer of relief from pain
Notably, the team also found evidence for the social transfer of relief from pain.

In these experiments, all the animals received an injection of a painful inflammatory substance, and then a portion of those mice also received morphine, which relieves pain.

It turned out that bystander mice that had received the injection of the painful substance showed less pain in response to pressure or heat after they interacted with animals that had also received morphine. Once again, optogenetics pointed to the ACC-NAc circuit as a key regulator of this surprising behavior.

“We honestly didn’t know if that kind of transfer of pain relief would work,” Smith said. “And we were shocked that the behavioral output of the mice looks as strong as the morphine analgesia [pain relief] that the other animals received. This is something we’d really like to look at further.”

More empathy, better pain treatment?
Mogil said he would like to see further study of other brain circuits that may help facilitate these “robust and fascinating behavioral outputs” in the animals. He noted that the activation of cells in the insula, another brain area implicated in pain, would be an interesting place to look in future studies. He also hopes to see the emergence of a better understanding of the differences between the social transfer of pain vs. pain relief.

“The big question is how this transfer occurs, and what might be different between the heightened pain sensitivity and the pain relief,” he said. “The researchers suggest it might be olfactory [relating to the sense of smell], and finding the chemosignals [chemical signals] that underlie this olfactory component would be very interesting.”

Malenka said that he does not think the ACC-NAc pathway is the only brain circuit involved in what is an extremely complicated social process. Yet, he does believe that as we learn more about these circuits, it will help us to better understand and perhaps even increase empathy in people.

He added that the findings might lead to improved pain treatments, either by highlighting new potential pain drug targets (molecules that drugs could alter to relieve pain), or by helping doctors and nurses find ways to better connect with chronic pain patients as they interact with them.

Malenka and Smith plan to test whether drugs that increase empathy, like 3,4-methyl​enedioxy​methamphetamine (MDMA) – more commonly known as ecstasy or molly – may enhance the social transfer effects.

“I’m not an expert in pain,” Malenka said, “but as a physician, I could see that empathy was important in treating my patients from my first year as a medical student. So, perhaps having an empathetic doctor could help with pain.”

“Similarly,” he continued, “some patients find relief with group therapy. Maybe that is due to the empathic experiences that are shared in that setting. Or there could be a drug that might help. We just don’t know yet. There are a lot of detailed mechanistic questions left for us to ask here, and the neural mechanisms we discover should help us better understand the nuances of these quite powerful social experiences.”

Kayt Sukel is a freelance writer based outside Houston, Texas.