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iNature
Pain is an evolutionarily conservative sensory and emotional response that serves as an early warning sign to protect the body from tissue damage or injury
.
However, the suffering caused by chronic pain can seriously affect the quality of life of patients diagnosed with chronic inflammatory diseases, including rheumatoid arthritis, multiple sclerosis, and inflammatory bowel diseases (IBDs), which are estimated to cost more than $6,000 per year to treat chronic pain billions
.
IBD is a group of chronic inflammatory diseases characterized by persistent inflammation of the entire or partial gastrointestinal
tract.
Abdominal pain is a common symptom of IBD and is thought to be caused by different mechanisms, including intestinal bloating, intestinal inflammation, and microbial dysregulation
.
Neuroepithelial crosstalk is essential
for intestinal physiology.
However, the mechanism by which sensory neurons communicate with epithelial cells and mediate intestinal barrier protection during homeostasis and inflammation is unclear
.
On October 14, 2022, David Artis' team at Cornell University published an online publication in Cell magazine titled " Nociceptor neurons direct goblet cells via a CGRP-RAMP1 axis to drive mucus production and gut barrier protection", the study found Nav1.
8 + CGRPP+ pain receptor neurons are juxtaposed with and signaled to intestinal goblet cells to drive mucus secretion and intestinal protection
.
Ablation of pain receptors results in decreased mucus thickness and biological dysregulation, while chemogenic pain receptor activation or capsaicin treatment induces mucus growth
.
Mouse and human goblet cells express the neuropeptide CGRP receptor Ramp1
.
Pain receptors signal via the CGRP-Ramp1 pathway, inducing rapid goblet cell emptying and mucus secretion
.
These results highlight the role
of intestinal neuralgia receptors in regulating the composition of the flora needed to inhibit inflammation and promote the protection of intestinal tissue.
sensory neurons that express transient receptor vanilloid 1 (TRPV1).
TRPV1 is a non-selective cation channel that can be activated
by a variety of stimuli, including heat, capsaicin, and inflammatory mediators.
Once activated, the nerve endings of the pain receptors release calcitonin gene-related peptides (CGRP, encoded by Calca), substance P ( SP, encoded by Tac1) and other neuropeptides, which can amplify or inhibit the downstream inflammatory cascade
.
Despite advances in understanding neuro-immune interactions, it remains unclear whether pain receptors regulate the development, severity, and/or or / of chronic inflammatory diseases such as IBD or play a role
in mitigation.
In this study, the researchers looked at the innervation of TRPV1+ pain receptors during homeostasis and inflammation in the gut of mice.
In mouse models of intestinal injury and inflammation, drug ablation targeting chemogenetic silencing, adenovirus-mediated colon-specific silencing, or TRPV1+ nociceptors resulted in increased susceptibility, suggesting that the TRPV1+ nociceptors that innervate the gut have a tissue-protective effect in these cases
。 In addition, brief silencing or permanent ablation of TRPV1+ pain receptors led to changes in the composition of the intestinal microbiota, and transplanted dysplastic mice aggravated intestinal damage and inflammation
in wild-type recipient mice.
Disruption of TRPV1+ nociceptorative-mediated histoprotective function with altered and selective colonization of gram-positive bacteria sterile (GF) with sufficient nociceptor (as opposed to nociceptor defect).
The association of mice with leather-positive clostridial bacteria promotes tissue protection
.
Importantly, chemical silencing or drug ablation of TRPV1+ pain receptors and therapeutic delivery of SP can reduce severe inflammation in analgesic-disrupted mice, thereby reducing pain receptor-derived SP levels
.
By further comparing with healthy controls, the researchers detected dysregulated patterns of TRPV1+ pain receptor innervation and included TRPV1 and TAC1 in intestinal biopsies of IBD patients The expression of genes associated with the pain receptor was altered, suggesting that dysregulation of pain sensation is an evolutionarily conserved feature
of chronic intestinal inflammation.
Notably, commensal microbes activate pain receptors to control the release
of homeostatic CGRP.
In the absence of pain receptors or epithelial Ramp1, mice exhibit increased epithelial stress and susceptibility to colitis
.
In contrast, administration of CGRP protects the algesicogeptors from eliminating resistance to colitis
in mice.
Pain receptor neurons drive mucus production and intestinal barrier protection through the CGRP-RAMP1 axis (Figure from Cell) In summary, this study identifies a previously unrecognized pathway through which TRPV1+ nociceptive receptors innervated by the intestine regulate the composition of the intestinal flora, mediating tissue-protective processes
against the background of persistent intestinal damage and inflammation.
By determining the microbiome-dependent and immunomodulatory effects of intestinal innervated pain receptors, it may be possible to have a positive effect The development of neuromodulation therapies and pain management strategies for IBD and other chronic inflammatory diseases has an impact
.
Original link: https://doi.
org/10.
1016/j.
cell.
2022.
09.
024
—END—
The content is 【iNature】
