Endosomal signalling of protease-activated receptor-2 amplifies histamine-induced pain of irritable bowel syndrome.

Endosomal PAR 2 signaling amplifies histamine-driven nociceptor sensitization in mouse colonic pain models, producing sustained hyperexcitability linked to IBS-like fecal supernatants.

• Why it matters: IBS pain is shaped by mast cell and bacterial co-release of proteases and histamine, but how protease activity sustains histamine’s otherwise transient pronociceptive effects is unclear.
• What they did: Using RNAscope, electrophysiology, and receptor/effector biophysics, the study tested PAR 2 and H 1 R coactivation in human and mouse dorsal root ganglion nociceptors, including intracolonic fecal supernatants and combined subthreshold trypsin plus histamine.
• The result: PAR 2 or H 1 R antagonists blocked fecal-supernatant–enhanced mechanosensitivity; trypsin pre-activation sensitized histamine responses in wild-type but not Par 2−/− mice, and endocytosis inhibitors prevented hypersensitivity, consistent with sustained endosomal PAR 2 signaling.

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