Study finds unexpected protective properties of pain

This study details steps in a complex signaling cascade and shows that pain neurons engage in direct crosstalk with mucus-laden enterocytes known as goblet cells.

“It turns out that pain may protect us in a more direct way than its classical job of detecting potential harm and sending signals to the brain.” shows how pain-mediating nerves in the gut talk to nearby epithelial cells lining the gut,” said the study’s senior investigator. Isaac Chiu, Associate Professor of Immunobiology at the Bravatnik Institute, HMS. “This means that the nervous system not only provides unpleasant sensations, but also plays a major role in the gut, and a key role in maintaining the gut barrier and protective mechanisms during inflammation. .”

direct conversation

Our intestines and airways are littered with goblet cells. Named for their cup-like appearance, goblet cells contain a gel-like mucus made of proteins and sugars that act as a protective coating that protects the organ’s surface from wear and tear.

A new study has found that intestinal goblet cells release protective mucus when triggered by direct interaction with pain-sensing neurons in the gut.

In a series of experiments, researchers observed that mice lacking pain neurons produced less protective mucus and experienced altered gut microbial composition.

To clarify how this protective crosstalk occurs, researchers analyzed the behavior of goblet cells in the presence and absence of pain neurons.

They found that the surface of goblet cells contains a class of receptors called RAMP1. This receptor ensures that cells can respond to neighboring pain neurons that are activated by dietary and microbial signals. Mechanical pressure, chemical stimulus, sudden temperature change, etc.

Experiments further showed that these receptors bind to a chemical called CGRP that is released from nearby pain neurons when neurons are stimulated. These RAMP1 receptors, which the researchers discovered, are also present in both human and mouse goblet cells and thus respond to pain signals.

Experiments further showed that the presence of specific gut microbes activates the release of CGRP to maintain gut homeostasis.

“This finding shows that these nerves are triggered not only by acute inflammation, but also at baseline,” Chiu said. The cells seem to release mucus.”

This feedback loop ensures that microbes signal neurons that regulate mucus, which keeps gut microbes healthy.

In addition to the presence of microorganisms, studies have shown that dietary factors also play a role in pain receptor activation. When the researchers gave mice capsaicin, the main ingredient in chili peppers known for its ability to induce intense and acute pain, pain neurons in mice were rapidly activated and goblet cells were activated. It released a large amount of protective mucus.

In contrast, mice lacking either pain neurons or goblet cell receptors for CGRP were susceptible to colitis, a form of intestinal inflammation. This finding could explain why people with intestinal flora are more prone to colitis.

When researchers gave animals lacking pain neurons the pain-signaling CGRP, the mice experienced a rapid improvement in mucus production. did.

This finding indicates that CGRP is a key driver of signaling cascades leading to secretion of protective mucus.

“Although pain is a common symptom of chronic inflammatory conditions of the gut such as colitis, our study shows that acute pain also has a direct protective role,” said the lead of the study. the author says. Yangdapyeonga postdoctoral researcher in the Qiu lab.

Downsides of pain control

The team’s experiments also showed that mice lacking pain receptors had worse colitis-induced damage when colitis developed.

Given that pain relievers are commonly used to treat patients with colitis, it may be important to consider the possible adverse consequences of blocking pain, the researchers said.

“If you have inflammation in your gut, one of the main symptoms is pain, so you may want to treat and block the pain to relieve it,” Chiu said. “But some of this pain signal may be directly protected as a neural reflex, raising important questions about how to carefully manage pain in ways that do not cause other harm.”

Furthermore, a class of common migraine drugs that inhibit CGRP signaling may damage the intestinal barrier tissue by interfering with this protective pain signaling, researchers say. says.

“Given that CGRP is a mediator of goblet cell function and mucus production, what would happen if we chronically blocked this protective mechanism in people with migraine and were taking these drugs long-term? ?” said Chiu. “Do drugs interfere with the mucosal lining and people’s microbiome?”

beyond the mucus

Goblet cells have multiple other functions in the intestine. They provide passage for antigens (proteins found in viruses and bacteria that initiate a protective immune response by the body) and produce antimicrobial chemicals that protect the gut from pathogens.

“One question that arises from our current study is whether pain fibers also modulate these other functions of goblet cells,” Yang said.

Another investigation, Yang said, is to look at disruptions in the CGRP signaling pathway to determine if it’s malfunctioning in patients with a genetic predisposition to inflammatory bowel disease.

Co-authors include Amanda Jacobson, Kimberly Meerschaert, Joseph Sifakis, Meng Wu, Xi Chen, Tiandi Yang, Youlian Zhou, Praju Vikas Anekal, Rachel Rucker, Deepika Sharma, Alexandra Sontheimer-Phelps, Glendon Wu, Liwen Deng, Michael Anderson, Includes Samantha. Choi, Dylan Neal, Nicole Lee, Dennis Kaspar, Bana Jabri, Jun Hu, Malin Johansson, Jay Chiagaraja, Samantha Riesenfeld.

This work was supported by the National Institutes of Health (grant R01DK127257, R35GM142683, P30DK034854, and T32DK007447). Food Allergy Science Initiative; Kenneth Rainin Foundation. Gastroenterology Research Core Center at the University of Chicago under grant P30 DK42086.

Jacobson is an employee of Genentech Inc. Chiu serves on the Scientific Advisory Boards of GSK Pharmaceuticals and Limm Therapeutics. His lab receives research support from Moderna Inc. and his Abbvie/Allergan Pharmaceuticals.