A53 NOVEL PROTEASE–HISTAMINE INTERACTIONS POTENTIATE PAIN SIGNALING EVOKED BY FECAL SUPERNATANTS FROM IBS PATIENTS

作者：N Jimenez Vargas, D A Gilmour, Badr Sokrat, Aidan S. Bennett, Alan Lomax, David E. Reed, Nigel W. Bunnett, S Vanner · 发表于：Journal of the Canadian Association of Gastroenterology · 年份：2025 · DOI：10.1093/jcag/gwae059.053 · 被引用次数：2 · 研究领域：Pharmacological Effects and Toxicity Studies、Pain Management and Opioid Use、Oral and gingival health research

Abstract Background Proteases and histamine, originating from intestinal tissue and/or the microbiota, have each been implicated in the severe pain symptoms reported by patients with irritable bowel syndrome (IBS). However, the effects of their combined signaling and the mechanisms involved have not been studied. Aims To determine whether histamine and trypsin synergistically enhance colonic nociceptive signaling and, if so, to study the mechanisms involved. Methods Fecal supernatants (FS) were obtained from IBS patients with low and high pain scores. Responses to luminal application of FS, histamine and protease (trypsin) and antagonists (H1R-pyrilamine, PAR2-GB83) were studied using ex vivo mouse colonic afferent nerve recordings. In mechanistic studies, excitability of isolated mouse dorsal root ganglia (DRG) neurons was measured using patch clamp recordings of rheobase after combined or sequential application of agonists. To study endosomal signaling, neurons were incubated with clathrin inhibitor, pitstop2, before agonists. Using HEK cells, recruitment of mGαq to PAR2 and H1R at the plasma membrane (CAAX) or early endosome (Rab5) was measured using bioluminescence resonance energy transfer (BRET) in response to sequential application of increasing doses of trypsin and histamine. Results In colonic afferent nerve recordings, FS from IBS patients with high pain scores increased mechanosensitivity (50%; p <0.001) and this was blocked by either a PAR2 and H1R antagoni...