Pain has been long recognized as certainly one of evolution’s most reliable tools to detect the presence of harm and signal that something is flawed -; an alert system that tells us to pause and concentrate to our bodies.

But what if pain is greater than only a mere alarm bell? What if pain is in itself a type of protection?

A latest study led by researchers at Harvard Medical School suggests that might be the case in mice.

The research, published Oct. 14 in Cell, shows that pain neurons within the mouse gut 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 steps of a fancy signaling cascade, showing that pain neurons engage in direct crosstalk with mucus-containing gut cells, generally known as goblet cells.

It seems that pain may protect us in additional direct ways than its classic job to detect potential harm and dispatch signals to the brain. Our work shows how pain-mediating nerves within the gut check with nearby epithelial cells that line the intestines. Because of this the nervous system has a serious role within the gut beyond just giving us an unpleasant sensation and that it is a key player in gut barrier maintenance and a protective mechanism during inflammation.”

Isaac Chiu, Study Senior Investigator, Associate Professor of Immunobiology, Blavatnik Institute at HMS

A direct conversation

Our intestines and airways are studded with goblet cells. Named for his or her cup-like appearance, goblet cells contain gel-like mucus product of proteins and sugars that acts as protective coating that shields the surface of organs from abrasion and damage. The brand new research found that intestinal goblet cells release protective mucus when triggered by direct interaction with pain-sensing neurons within the gut.

In a set of experiments, the researchers observed that mice lacking pain neurons produced less protective mucus and experienced changes of their intestinal microbial composition -; an imbalance in useful and harmful microbes generally known as dysbiosis.

To make clear just how this protective crosstalk occurs, the researchers analyzed the behavior of goblet cells within the presence and within the absence of pain neurons.

They found that the surfaces of goblet cells contain a style of receptor, called RAMP1, that ensures the cells can reply to adjoining pain neurons, that are activated by dietary and microbial signals, in addition to mechanical pressure, chemical irritation or drastic changes in temperature.

The experiments further 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 each human and mouse goblet cells, thus rendering them aware of pain signals.

Experiments further showed that the presence of certain gut microbes activated the discharge of CGRP to take care of gut homeostasis.

“This finding tells us that these nerves are triggered not only by acute inflammation, but additionally at baseline,” Chiu said. “Just having regular gut microbes around appears to tickle the nerves and causes the goblet cells to release mucus.”

This feedback loop, Chiu said, ensures that microbes signal to neurons, neurons regulate the mucus, and the mucus keeps gut microbes healthy.

Along with microbial presence, dietary aspects also played a job in activating pain receptors, the study showed. When researchers gave mice capsaicin, the primary ingredient in chili peppers known for its ability to trigger intense, acute pain, the mice’s pain neurons got swiftly activated, causing goblet cells to release abundant amounts of protective mucus.

Against this, mice lacking either pain neurons or goblet cell receptors for CGRP were more prone to colitis, a type of gut inflammation. The finding could explain why individuals with gut dysbiosis could also be more vulnerable to colitis.

When researchers gave pain-signaling CGRP to animals lacking pain neurons, the mice experienced rapid improvement in mucus production. The treatment protected mice against colitis even within the absence of pain neurons.

The finding demonstrates that CGRP is a key instigator of the signaling cascade that results in the secretion of protective mucus.

“Pain is a typical symptom of chronic inflammatory conditions of the gut, comparable to colitis, but our study shows that acute pain plays a direct protective role as well,” said study first creator Daping Yang, a postdoctoral researcher within the Chiu Lab.

A possible downside to suppressing pain

The team’s experiments showed that mice lacking pain receptors also had worse damage from colitis when it occurred.

Provided that pain medications are sometimes used to treat patients with colitis, it could be essential to think about the possible detrimental consequences of blocking pain, the researchers said.

“In individuals with inflammation of the gut, certainly one of the main symptoms is pain, so you would possibly think that we might wish to treat and block the pain to alleviate suffering,” Chiu said. “But some a part of this pain signal might be directly protective as a neural reflex, which raises essential questions on learn how to fastidiously manage pain in a way that doesn’t result in other harms.”

Moreover, a category of common migraine medications that suppress the secretion of CGRP may damage gut barrier tissues by interfering with this protective pain signaling, the researchers said.

“Provided that CGRP is a mediator of goblet cell function and mucus production, if we’re chronically blocking this protective mechanism in individuals with migraine and in the event that they are taking these medications long-term, what happens?” Chiu said. “Are the drugs going to interfere with the mucosal lining and other people’s microbiomes?”

Goblet cells have multiple other functions within the gut. They supply a passage for antigens -; proteins found on viruses and bacteria that initiate a protective immune response by the body -; and so they produce antimicrobial chemicals that protect the gut from pathogens.

“One query that arises from our current work is whether or not pain fibers also regulate these other functions of goblet cells,” Yang said.

One other line of inquiry, Yang added, can be to explore disruptions within the CGRP signaling pathway and determine whether malfunctions are at play in patients with genetic predisposition to inflammatory bowel disease.

Source:

Journal reference:

Yang, D., et al. (2022) Nociceptor neurons direct goblet cells via a CGRP-RAMP1 axis to drive mucusproduction and gut barrier protection. Cell. doi.org/10.1016/j.cell.2022.09.024.