Pain has long been recognized as one of evolution’s most reliable tools for detecting damage and signaling that something is wrong – an alert system that tells us to stop and pay attention to our bodies.
But what if pain were more than just a wake-up call? What if pain is itself a form of protection?
A new study by researchers at Harvard Medical School suggests it may be the case with mice.
The research, published on 14 October a Cellshows that pain neurons in the mouse intestine regulate the presence of protective mucus under normal conditions and stimulate intestinal cells to release more mucus during states of inflammation.
The work details the stages of a complex signal cascade, demonstrating that pain neurons engage in direct crosstalk with intestinal mucus-containing cells, known as goblet cells.
“It turns out that pain can protect us in more direct ways than its classic job of detecting potential damage and sending signals to the brain. Our work shows how pain-mediating nerves in the gut talk to neighboring epithelial cells lining the ‘intestine”. said study senior researcher Isaac Chiu, an associate professor of immunobiology at HMS’s Blavatnik Institute. “This means that the nervous system plays an important role in the intestine as well as giving us an unpleasant sensation and that it is a key player in maintaining the intestinal barrier and a protective mechanism during inflammation.”
A direct conversation
Our intestines and airways are studded with goblet cells. Named for their cup-shaped appearance, goblet cells contain gelatinous mucus made of proteins and sugars that acts as a protective coating that protects the surface of the organs from abrasion and damage. The new research has found that intestinal goblet cells release protective mucus when activated by direct interaction with pain-sensitive neurons in the gut.
In a series of experiments, the researchers observed that mice lacking pain neurons produced less protective mucus and experienced changes in their gut microbial makeup, an imbalance in beneficial and harmful microbes known as dysbiosis.
To clarify how this protective crosstalk occurs, the researchers analyzed the behavior of goblet cells in the presence and absence of pain neurons.
They found that the surfaces of goblet cells contain a type of receptor, called RAMP1, which ensures that the cells can respond to adjacent pain neurons, which are activated by dietary and microbial signals, as well as mechanical pressure, chemical irritation, or fluctuations. temperature drastic.
The experiments also showed that these receptors connect with a chemical called CGRP, released by nearby pain neurons, when the neurons are stimulated. These RAMP1 receptors, the researchers found, are also present in human and mouse goblet cells, thus making them reactive to pain signals.
The experiments also showed that the presence of certain intestinal microbes triggered the release of CGRP to maintain intestinal homeostasis.
“This finding tells us that these nerves are activated not only by acute inflammation but also at baseline,” Chiu said. “Just having regular gut microbes around seems to tickle the nerves and cause the goblet cells to release mucus.”
This feedback loop, Chiu said, ensures that microbes signal to neurons, neurons regulate mucus, and mucus keeps gut microbes healthy.
In addition to microbial presence, the study showed that dietary factors also played a role in activating pain receptors. When the researchers gave the mice capsaicin, the main ingredient in chillies known for its ability to trigger intense, sharp pain, the mice’s pain neurons fired quickly, causing the release of copious amounts of protective mucus. by the goblet cells.
In contrast, mice lacking pain neurons or goblet cell receptors for CGRP were more susceptible to colitis, a form of intestinal inflammation. The finding could explain why people with intestinal dysbiosis may be more prone to colitis.
When the researchers administered pain-signaling CGRPs to animals lacking pain neurons, the mice experienced rapid improvement in mucus production. The treatment protected the mice from colitis even in the absence of pain neurons.
The discovery demonstrates that CGRP is a key instigator of the signaling cascade leading to protective mucus secretion.
“Pain is a common symptom of chronic inflammatory bowel conditions, such as colitis, but our study shows that acute pain also plays a direct protective role,” said study first author Daping Yang, postdoctoral researcher. in the Chiu Lab.
A possible downside to pain suppression
The team’s experiments showed that even mice lacking pain receptors suffered worse damage from colitis when it occurred.
Given that pain medications are often used to treat patients with colitis, it may be important to consider the possible harmful consequences of pain blocking, the researchers said.
“In people with bowel inflammation, one of the main symptoms is pain, so you might think we’d like to treat and block the pain to relieve the pain,” Chiu said. “But some of this pain signal could be directly protective as a neural reflex, which raises important questions about how to carefully manage pain in a way that doesn’t lead to other harm.”
Additionally, a class of common migraine medications that suppress CGRP secretion can damage intestinal barrier tissues by interfering with this protective pain signaling, the researchers said.
“Since CGRP is a mediator of goblet cell function and mucus production, if we are chronically blocking this protective mechanism in people with migraines and are taking these drugs long-term, what happens?” Chiu said. “Will drugs interfere with the mucosal lining and microbiomes of people?”
Goblet cells have multiple other functions in the intestine. They provide a gateway for antigens – proteins found on viruses and bacteria that initiate a protective immune response from the body – and produce antimicrobial chemicals that protect the gut from pathogens.
“A question that arises from our current work is whether pain fibers also regulate these other goblet cell functions,” Yang said.
Another line of investigation, Yang added, would be to explore disruptions in the CGRP signaling pathway and determine whether malfunctions are at play in patients with a genetic predisposition to inflammatory bowel disease.
The work was supported by the National Institutes of Health (grants R01DK127257, R35GM142683, P30DK034854 and T32DK007447); the Food Allergy Science Initiative; the Kenneth Rainin Foundation; and the Digestive Diseases Research Core Center with grant P30 DK42086 from the University of Chicago.
Jacobson is an employee of Genentech Inc .; Chiu sits on the scientific advisory committees of GSK Pharmaceuticals and Limm Therapeutics. His lab receives research support from Moderna Inc. and Abbvie / Allergan Pharmaceuticals.