Transient receptor potential ion channel function in sensory transduction and cellular signaling cascades underlying visceral hypersensitivity

Visceral hypersensitivity is an important mechanism underlying increased abdominal pain perception in functional gastrointestinal disorders including functional dyspepsia, irritable bowel syndrome, and inflammatory bowel disease in remission. Although the exact pathophysiological mechanisms are poorly understood, recent studies described upregulation and altered functions of nociceptors and their signaling pathways in aberrant visceral nociception, in particular the transient receptor potential (TRP) channel family. A variety of TRP channels are present in the gastrointestinal tract (TRPV1, TRPV3, TRPV4, TRPA1, TRPM2, TRPM5, and TRPM8), and modulation of their function by increased activation or sensitization (decreased activation threshold) or altered expression in visceral afferents have been reported in visceral hypersensitivity. TRP channels directly detect or transduce osmotic, mechanical, thermal, and chemosensory stimuli. In addition, pro-inflammatory mediators released in tissue damage or inflammation can activate receptors of the G protein-coupled receptor superfamily leading to TRP channel sensitization and activation, which amplify pain and neurogenic inflammation. In this review, we highlight the present knowledge on the functional roles of neuronal TRP channels in visceral hypersensitivity and discuss the signaling pathways that underlie TRP channel modulation. We propose that a better understanding of TRP channels and their modulators may facilitate the development of more selective and effective therapies to treat visceral hypersensitivity.status: publishe

Staphylococcal enterotoxin B triggers a bystander immune response to food antigens leading to visceral hypersensitivity

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Evidence for TRP channel sensitization in IBS with histamine 1 receptor antagonism as effective treatment

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Evidence for histamine-mediated sensitization of TRPV1 signaling in sensory neurons in mice and IBS patients

Background & Aims: Mast cell activation and neuronal sensitization through TRPV1 have been proposed to underlie visceral hypersensitivity in patients with irritable bowel syndrome (IBS). We recently showed that 12 weeks of treatment with the H1R antagonist ebastine significantly improved abdominal pain and global relief compared to placebo. As histamine released by mast cells activates afferent nerves through histamine 1 receptors (H1R), and we recently showed increased pain responses to rectal application of capsaicin in IBS, we hypothesized that histamine could be one of the mediators sensitizing TRPV1, a mechanism prevented by H1R blockade and potentially contributing to the therapeutic effect of ebastine. Methods: The submucosal plexus was isolated from rectal biopsies taken from 16 healthy volunteers (HV) and 12 IBS patients and responses to exogenously applied capsaicin (0.1, 1 and 10 nM) and histamine (1, 10 and 100 µM) were monitored using calcium (Ca2+)-imaging. In addition, the effect of 10 µM histamine pre-incubation on the capsaicin response was studied in HV. In parallel, murine dorsal root ganglia (DRG) were isolated to study the calcium response to capsaicin (10 – 250 nM) in the presence of histamine or after overnight incubation with mucosal biopsy supernatant from HV and IBS patients. Pyrilamine (1 µM) was used as H1R antagonist. Results: Application of histamine and capsaicin evoked significantly higher peak amplitudes in submucosal neurons from IBS patients compared to HV (Table 1). Pretreatment with histamine significantly increased the peak amplitudes in response to capsaicin in submucosal neurons from HV (Table 1). This sensitization of TRPV1 by histamine was confirmed in mouse DRG neurons, an effect that was prevented by preincubation with pyrilamine (Table 2). In parallel studies, overnight incubation with HV supernatant spiked with 10 µM histamine significantly increased the response to capsaicin compared to control HV supernatant. Similarly, overnight exposure of DRG neurons to IBS supernatant significantly increased the capsaicin response, an effect that was reduced by pyrilamine (Table 2). Conclusion: We showed that submucosal neurons of IBS patients are more intensely activated by capsaicin than those of HV. This effect can be mimicked by preincubation with histamine in both human submucosal neurons and mouse DRG neurons. Furthermore, incubation of mouse DRG neurons with IBS supernatant also increases the response to TRPV1, an effect that is blocked by the H1R antagonist pyrilamine. Based on these data, we conclude that histamine sensitizes TRPV1 on sensory neurons, most likely contributing to increased visceral pain perception in IBS. Moreover, we hypothesize that the therapeutic effect of the H1R antagonist ebastine in IBS patients can at least partly be explained by interference with this pathway.status: publishe

Upregulation of mast cell related genes in Irritable Bowel Syndrome.

Poster presentationstatus: Published onlin

Neuronal sensitization of TRPV1 by histamine mediated by histamine 1 receptor in an unique cohort of PI-IBS patients

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Histamine-mediated potentiation of TRPA1 and TRPV4 signaling in submucosal neurons in IBS patients.

Previously, we showed histamine-mediated sensitization of transient receptor potential (TRP) vanilloid 1 (TRPV1) in patients with irritable bowel syndrome (IBS). Sensitization of TRP ankyrin 1 (TRPA1) and TRP vanilloid 4 (TRPV4) are also involved in aberrant pain perception in preclinical models of somatic pain. Here, we hypothesize that in parallel with TRPV1, histamine sensitizes TRPA1 and TRPV4, contributing to increased visceral pain in patients with IBS. Rectal biopsies were collected from patients with IBS and healthy subjects (HS) to study neuronal sensitivity to TRPA1 and TRPV4 agonists (cinnamaldehyde and GSK1016790A) using intracellular Ca2+ imaging. In addition, the effect of supernatants of rectal biopsies on patients with IBS and HS was assessed on TRPA1 and TRPV4 responses in murine dorsal root ganglion (DRG) sensory neurons. Finally, we evaluated the role of histamine and histamine 1 receptor (H1R) in TRPA1 and TRPV4 sensitization. Application of TRPA1 and TRPV4 agonists evoked significantly higher peak amplitudes and percentage of responding submucosal neurons in biopsies of patients with IBS compared with HS. In HS, pretreatment with histamine significantly increased the Ca2+ responses to cinnamaldehyde and GSK1016790A, an effect prevented by H1R antagonism. IBS supernatants, but not of HS, sensitized TRPA1 and TRPV4 on DRG neurons. This effect was reproduced by histamine and prevented by H1R antagonism. We demonstrate that the mucosal microenvironment in IBS contains mediators, such as histamine, which sensitize TRPV4 and TRPA1 via H1R activation, most likely contributing to increased visceral pain perception in IBS. These data further underscore H1R antagonism as potential treatment for IBS. NEW & NOTEWORTHY We provide evidence for histamine-mediated transient receptor potential (TRP) ankyrin 1 and TRP vanilloid 4 sensitization in irritable bowel syndrome (IBS) via histamine 1 receptor (H1R) activation, most likely contributing to increased visceral pain perception. Our results reveal a general role of sensory TRP channels as histamine effectors in the pathophysiology of IBS and provide novel mechanistic insights into the therapeutic potential of H1R antagonism in IBS.status: Published onlin

Food Antigen-specific Sensitization of Nociceptive Nerves as an Underlying Mechanism of Visceral Pain in IBS

Oral presentationstatus: publishe