Nov. 16, 2022 Pain is how our bodies tell us something’s wrong, alerting us to injury or infection and helping doctors make a diagnosis. But pain is not fun, so we often try to block it using medication. 

But a surprising new study led by Harvard Medical School researchers suggests that blocking acute pain may actually lead to pain in the gut. 

That’s because pain may be a key part of a process that protects the gut from damage. 

In the study, pain neurons in mice helped regulate the protective mucus that lines the gut, releasing more mucus in response to inflammation. 

“These neurons signal to the goblet cells in the gut that make mucus,” says study senior investigator Isaac Chiu, PhD, an associate professor of immunobiology at Harvard’s Blavatnik Institute. “This is very important because mucus protects the gut barrier from potential harmful microbes and tissue injury.” 

Messing with that process could lead to dysbiosis, an imbalance in the gut, paving the way for inflammation and raising the risk of painful gut conditions such as inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS), Chiu says.

What the Researchers Did

In the study, researchers bred mice that lacked pain neurons. These mice produced less protective mucus, and “their gut microbiome became dysregulated,” Chiu says. “They also became more susceptible to colitis" (inflammation in the gut marked by belly pain and bowel issues). 

To find out why, the researchers took a close look at those mucus-producing goblet cells. They found that the cells contain a receptor, called RAMP1, that helps them respond to pain. This receptor is activated by a neuropeptide called CGRP, which is released by pain neurons in response to pain. 

Without that CGRP or those receptors, the gut won’t get the message to produce more mucus – and mucus production declines.

“We need this signal to maintain a healthy gut,” says Chiu.

Particularly concerning are a class of migraine medications that suppress CGRP, Chiu notes. 

“If we target CGRP long-term, it could cause defective gut mucosal health, including loss of good microbes and increased susceptibility to inflammation," he says. 

What’s more, given that pain meds are often used to treat patients with colitis, considering the possible harmful effects may be important, the researchers say.

Why This Matters

The study builds on growing research on “inter-organ communication,” how molecules in the body interact between organs to help us maintain health. It sheds light on the gut-brain axis, signaling between the GI tract and the central nervous system. 

“Acute pain is designed to protect us from damage, so it makes sense that it could be coupled to secretion of mucus,” says Chiu. “If we lose this signal, we are more likely to have an injured or inflamed gut.”

On the other hand, too much pain signaling is likely not helpful either. 

“Chronic pain is on the other side of the coin,” Chiu says. “We need to find ways to keep the good aspects of pain signaling, such as maintaining gut homeostasis, and shut down the perception of pain in the brain, which is the part that makes people suffer.”

That means better understanding the things that control pain signaling in the gut, so we can “tune it down” without completely shutting it off, he says. 

More research is needed to confirm the findings in humans. But depending on how the research unfolds, this could change the way we manage pain and open the door to new treatments for patients with gut conditions, Chiu says. 

In the meantime, improving your gut health may help regulate the pain-signaling process, Chiu notes. Healthy microbes may stimulate pain fibers just enough to maintain mucus without contributing to gut pain. You can feed healthy gut microbes by eating more fiber and fermented foods, and cutting back on fried foods and red meat. Exercise, managing stress, and getting outside can help, too. 

Show Sources

SOURCES: 

Isaac Chiu, PhD, associate professor of immunobiology, Harvard’s Blavatnik Institute. 

Cell: "Nociceptor neurons direct goblet cells via a CGRP-RAMP1 axis to drive mucus production and gut barrier protection."

 

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