Unexpected protective properties of pain

Summary: Painful neurons engage in direct talk with goblet cells, or mucus-containing cells within the gut. During inflammatory states, pain cells stimulate the goblet cells to release more mucus. The results suggest that the nervous system plays a key role in gut barrier maintenance and triggers protective mechanisms during periods of inflammation.

source: Harvard

Pain has long been recognized as one of evolution’s most reliable tools for detecting damage and signaling something is wrong – an alert system that tells us to stop and pay attention to our bodies.

But what if the pain was more than just an alarm bell? What if the pain itself was a form of protection?

A new study led by researchers at Harvard Medical School suggests that this may be the case in mice.

The research was published on October 14 in cellAnd the It shows that painful neurons in the mouse gut regulate the presence of protective mucus under normal conditions and stimulate gut cells to release more mucus during inflammatory states.

The work details the steps of a complex signaling cascade, demonstrating that nociceptive neurons participate in direct crosstalk with mucus-containing gut cells, known as goblet cells.

“It turns out that pain may protect us in more direct ways than its traditional function of detecting potential damage and sending signals to the brain. Our work demonstrates how the nerves that mediate pain in the intestine talk to nearby epithelial cells that line the intestine,” said the study’s lead researcher. Isaac Chiu, Associate Professor of Immunobiology at the Blavatnik Institute at HMS. “This means that the nervous system has a key role in the gut that goes beyond just giving us an unpleasant sensation and is a major player in gut barrier maintenance and a protective mechanism during inflammation.”

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Our intestines and airways are studded with goblet cells. The goblet cells, named for their cup-like appearance, contain a gel-like mucus made of proteins and polysaccharides that acts as a protective layer that protects the surface of the organs from abrasion and damage. The new research found that intestinal goblet cells secrete protective mucus when stimulated by direct interaction with pain-sensing neurons in the gut.

In a set of experiments, the researchers observed that mice lacking painful neurons produced less protective mucus and had changes in their intestinal microbial composition — an imbalance of both 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 painful neurons.

They found that the surfaces of the goblet cells contain a type of receptor called RAMP1, which ensures the cells respond to neighboring painful neurons, which is activated by nutritional and microbial signals, as well as mechanical stress, chemical irritation or drastic changes in temperature. .

The experiments further showed that these receptors attach to a chemical called CGRP, which is released by nearby pain neurons, when the neurons are stimulated. The researchers found that RAMP1 receptors are also present in both human and mouse goblet cells, causing them to respond to pain signals.

The experiments also showed that the presence of certain gut microbes activated the release of CGRP to maintain gut homeostasis.

“This finding tells us that these nerves result not only from acute inflammation, but also at baseline,” Chiu said. The mere presence of the gut microbiome appears to jostle the nerves and cause the goblet cells to secrete mucus.

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

The study showed that in addition to the microbial presence, dietary factors also played a role in the activation of pain receptors. When researchers gave mice capsaicin, the main ingredient in hot peppers known to cause sharp, sharp pain, the mice’s pain neurons rapidly activated, causing the goblet cells to release copious amounts of protective mucus.

By contrast, mice lacking neurites or goblet cell receptors were more likely to develop colitis, a form of intestinal inflammation. This finding could explain why people with intestinal dysbacteriosis are more likely to develop colitis.

When the researchers gave CGRP signals to animals lacking painful neurons, the mice experienced a rapid improvement in mucus production. The treatment protects mice from colitis even in the absence of painful neurons.

The discovery demonstrates that CGRP is the main inducer of the signaling cascade that leads to the secretion of protective mucus.

“Pain is a common symptom of chronic inflammatory conditions in the gut, such as colitis, but our study shows that acute pain plays a direct protective role as well,” said the study’s first author. daping yanga postdoctoral researcher in the Chiu Lab.

Possible downside to pain relief

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

The researchers said that given that pain medications are often used to treat patients with colitis, it may be important to consider the potential adverse consequences of preventing pain.

“For people with IBD, pain is a major symptom, so you might think we want to treat and stabilize the pain to ease the suffering,” Chiu said. “But part of this pain signal can be directly protective as a neural response, which raises important questions about how to carefully manage pain in a way that does not lead to further damage.”

Additionally, the researchers said, a class of common migraine medications that inhibit CGRP secretion may damage gut barrier tissue by interfering with protective pain signals.

This shows goblet cells and nerves
Harvard Medical School researchers analyzed molecular crosstalk between pain fibers in the intestine and the goblet cells that line the intestinal walls. The work shows that chemical signals from pain neurons stimulate goblet cells to release protective mucus that coats the intestines and protects it from damage. The results show that intestinal pain is not just a detection and signaling system, but plays a direct protective role in the gut. Credit: Chiu Lab/Harvard Medical School

“Given that CGRP is a mediator of goblet cell function and mucus production, if we chronically block this protective mechanism in people with migraines and if they take these drugs long-term, what happens?” Chiu said. Will the drugs interfere with the mucosal lining and microbiome of humans?

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

“One of the questions that arises from our current work is whether pain fibers also regulate these other functions of goblet cells,” Yang said.

Another line of inquiry, Yang added, is to explore disruptions in the CGRP signaling pathway and determine whether malfunctions play a role in patients with a genetic predisposition to IBD.

Co-authoring, funding and disclosures

Co-authors included Amanda Jacobson, Kimberly Merchert, Joseph Sivakis, Meng Wu, Qi Chen, Tiandi Yang, Julian Zhou, Praju Vikas Anikal, Rachel Rucker, Deepika Sharma, Alexandra Sontheimer Phelps, Glendon Wu, Lewin Deng, Michael Zhou, and Michael Andersen. and Dylan Neal, Nicole Lee, Dennis Kasper, Bana Gebre, John Huh, Malin Johansson, Jay Thiagarajah and Samantha Riesenfeld.

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

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 Abbvie/Allergan Pharmaceuticals.

About this news The search for pain

author: Ekaterina Besheva
source: Harvard
Contact: Ekaterina Besheva – Harvard
picture: Image credited to Chiu Lab / Harvard Medical School

original search: Access closed.
Pain receptor neurons direct goblet cells through the CGRP-RAMP1 axis to drive mucus production and protect the gut barrier.Written by Daping Yang et al. cell


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Pain receptor neurons direct goblet cells through the CGRP-RAMP1 axis to drive mucus production and protect the gut barrier.


  • Mobility 1.8+CGRP+ Goblet cells adjacent to pain receptors and stimulate rapid mucus secretion
  • Commensals trigger the release of CGRP, which signals Ramp1 expressed by goblet cells
  • Eradication of Nociceptor or Ramp1 results in decreased mucus levels and bacterial dysbiosis
  • Goblet cell neural signaling via the CGRP-Ramp1 axis protects against colitis


Neuroepithelial crosstalk is critical to gut physiology. However, the mechanisms by which sensory neurons communicate with epithelial cells to mediate protection of the gut barrier at homeostasis and during inflammation are not well understood.

Here, we find that Nav1.8+CGRP+ Pain receptor neurons are positioned alongside intestinal goblet cells and signaled to drive mucus secretion and protect the intestine. Ablation of pain receptors decreased mucus thickness and dysbiosis, while activation of chemoreceptors or capsaicin treatment led to mucus growth.

Mouse cells and human cells expressed Ramp1, the CGRP neuropeptide receptor. Pain receptors signal via the CGRP-Ramp1 pathway to induce rapid goblet cell emptying and mucus secretion.

Notably, commensal microbes activate pain receptors to control homologous CGRP release. In the absence of epithelial pain or Ramp1 receptors, mice showed increased epithelial stress and susceptibility to colitis. Conversely, administration of CGRP protected the resected mice from colitis.

Our findings demonstrate a goblet axon regulating the protection of the gut mucosal barrier.

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