Cell: Pain has an unexpected protective effect

Pain has long been considered one of the most reliable tools in evolution to detect the presence of injury and signal something is wrong with our body — an alert system that reminds us to stop and pay attention to our bodies
.

What if pain wasn't just a wake-up call? What if pain itself is a form of protection?

A team of researchers led by Harvard Medical School found that this is likely to happen in
mice.
The study, published in Cell, showed that pain-sensing neurons in the gut of mice normally regulate the presence of protective mucus and stimulate intestinal cells to release more mucus
in an inflammatory state.

This work details the individual steps of a complex signaling cascade, showing how pain-sensing neurons interact directly with mucus-containing intestinal cells (goblet
cells).

Corresponding author Isaac Chiu, associate professor of immunology at Harvard Medical School, said: "It turns out that pain may protect us in a more direct way than just detecting potential harm and sending signals
to the brain.
Our work shows how pain-regulating nerves
in the gut communicate with epithelial cells lining the intestine.
This means that the nervous system plays an important role in the gut, and in addition to giving us unpleasant sensations, it also plays a role
in maintaining the intestinal barrier and inflammation protection mechanisms.
”

Direct conversation

Our intestines and respiratory tract are full of goblet cells
.
Named for its cup-like appearance, these cells contain gelatinous mucus (made up of proteins and sugars) that acts as a protective coating that protects the surface of the organ from wear and damage
.
The new study found that protective mucus is released when the goblet cells of the gut interact directly with pain-sensing neurons
.

Through a series of experiments, the researchers observed that mice lacking pain-sensing neurons produced less protective mucus and changed the composition of the gut microbiome — an imbalance between beneficial and harmful microbes known as gut dysbiosis
.

To figure out how this protective interaction occurs, the researchers analyzed the behavior
of goblet cells when pain-sensing neurons are present and absent.

They found that the surface of goblet cells contains a receptor called RAMP1, which ensures that goblet cells respond to neighboring pain-sensing neurons that are activated
by dietary and microbial signals, mechanical stress, chemical stimulation, or drastic temperature changes.

The experiments further showed that when pain-sensing neurons are stimulated, a chemical called CGRP is released, which interacts with the RAMP1 receptor
.
The presence of certain gut microbes activates the release of CGRP to maintain homeostasis
in the gut.

"This finding tells us that these neurons are triggered not only by acute inflammation, but also at baseline," Chiu said
.
"As long as there are normal gut microbes around, it seems to stimulate neurons and prompt goblet cells to release mucus
.
"

This feedback loop ensures that gut microbes send signals to neurons, which regulate mucus secretion, which keeps the gut microbes healthy
.

In addition to the presence of microorganisms, dietary factors also play a role
in activating pain receptors.
When the researchers fed capsaicin to mice, the mice's pain-sensing neurons activated rapidly, causing goblet cells to release large amounts of protective mucus
.
Capsaicin is the main component in chili peppers and can trigger severe acute pain
.

In contrast, mice lacking pain-sensing neurons or goblet cell receptors were more likely to develop colitis
.
This finding may explain why people with dysbiosis are more likely to develop colitis
.

When the researchers injected the pain signal CGRP into animals lacking pain-sensing neurons, the mice's mucus secretion improved
rapidly.
Even in the absence of pain-sensing neurons, this treatment was able to protect the mice from colitis
.
This finding suggests that CGRP is a key stimulatory factor
in the signaling cascade that promotes protective mucus secretion.

"Pain is a common symptom of chronic inflammation of the gut, such as colitis, but our study shows that acute pain also plays a direct protective role," said
Daping Yang, the study's first author and a postdoc in Chiu's lab.

Suppress the "side effects" of pain

Experiments also showed that when colitis occurs, mice lacking pain receptors are more severely harmed
.
The researchers say that given the usual use of painkillers to treat colitis, serious consideration needs to be given to the potentially harmful consequences
of blocking pain.

"Pain is one of the main symptoms in people with intestinal inflammation, so doctors may block the pain to reduce the pain
," Chiu said.
"But this pain signal may act directly as a nerve reflex, which raises an important question about how to carefully manage pain without causing other injuries
.
"

In addition, the researchers say, a class of migraine drugs that inhibit CGRP secretion may interfere with this protective pain signal, which in turn destroys the intestinal barrier tissue
.

"CGRP is an intermediary between goblet cells and mucus production, and if we block this protective mechanism for migraine sufferers for a long time, what will happen to them after taking these drugs for a long time?" Chiu said
.
"Do these drugs interfere with the lining of the mucosa and the microbiome of the human body?"

Yang added that another research direction is to explore the disruption of CGRP signaling pathways and determine whether functional impairment
is present in susceptible patients with inflammatory bowel disease.

Original text search

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