105: P75NTR in Enteric Glia Mediates Inflammatory Visceral Hypersensitivity via the COX-2/PGE2/EP4 Axis

Topic: Basic Science
Subtopic: Non-specific to any diagnosis (including studies in healthy animals), Pharmacological interventions, Omics (Proteomics/Metabolomics/Transcriptomics/Genomics), Transgenic models

Background and Aims: Intestinal inflammation often results in debilitating and poorly controlled abdominal pain. While sensory neurons are known to transmit these pain signals, the role of the surrounding enteric glial cells (EGCs) in modulating visceral nociception remains unclear. This study aims to investigate how p75 neurotrophin receptor (p75NTR) signaling in EGCs contributes to visceral hypersensitivity and to identify the underlying molecular mechanisms by which glia-neuron communication facilitates pain sensitization during inflammation.

Methods: We utilized an acetic acid-induced visceral pain mouse model. ScRNA-seq was performed to identify glial subpopulations and signaling pathways. We integrated chemogenetic activation of EGCs with ex vivo calcium imaging of sensory nerve terminals to assess functional connectivity. The pathological significance of the p75NTR pathway was further validated using enteric glia-specific p75NTR knockout mice and pharmacological inhibitors targeting p75NTR.

Results: We found that p75NTR activation in EGCs promotes visceral pain by secreting factors that sensitize gut-innervating nociceptors. ScRNA-seq revealed that IL-1β is primarily produced by a p75NTR+ glial subset, which enhances the opening of Cx43 hemichannels. This process leads to increased COX-2 abundance and the release of Prostaglandin E2 (PGE2), subsequently activating EP4 receptors on sensory terminals. Notably, chemogenetic activation of p75NTR+ glia sensitized nociceptors only under inflammatory conditions. Both pharmacological blockade and genetic deletion of glial p75NTR significantly attenuated IL-1β -induced visceral hypersensitivity.

Conclusions: Our findings demonstrate that p75NTR+ enteric glia act as pivotal mediators of inflammatory visceral pain. The p75NTR-mediated glial-neuronal signaling axis, specifically involving the COX-2/PGE2/EP4 pathway, drives the sensitization of sensory neurons. These results suggest that targeting enteric glia-specific signaling pathways represents a promising therapeutic strategy for alleviating chronic visceral pain associated with inflammatory bowel diseases.

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Presenting Author: Zha anhui
Submitting Author: Anhui Zha

Senior Author: Dai Ruping

IASP 2026 Global Year theme of Neuropathic Pain: Yes