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

Abstract

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.

Newly developed serine protease inhibitors decrease visceral hypersensitivity in a post‐inflammatory rat model for irritable bowel syndrome

“…Previously, Cattaruzza et al (2010) already demonstrated that TRPA1 channels mediate PAR2induced visceral hypersensitivity. Thus, our results fit in the general hypothesis described in the review by Balemans et al (2017).…”

“…We hypothesize that the compounds used in our study directly inhibit serine proteases early in the signalling cascade, thereby preventing the proteases from activating PARs which, in turn, cannot sensitize TRP channels, thereby preventing visceral hypersensitivity. A recent review on TRP channels reports that pro‐inflammatory mediators, including 5‐HT, histamine, bradykinins and proteases can activate various GPCRs such as PAR receptors, thereby triggering TRP channel sensitization in visceral hypersensitivity (Balemans et al ., ). To investigate this hypothesis further in our model, we assessed the mRNA expression of PARs and TRP channels, which play a role in visceral hypersensitivity and serine protease downstream signalling pathways, at the colonic level and at DRGs.…”

Transient Receptor Potential Channels and Inflammatory Bowel Disease

“…TRPV4 colocalizes with TRPV1, TRPA1, and protease-activated receptors 2 (PAR-2) in the GI tract, in response to strong acidosis, hypotonicity, warmth, and mechanical stimuli (10,11). TRPM2 is sensitive to heat stimulus while TRPM8 is essential to cold-induced pain (12). Most of TRP channels are non-selective cation channels and show the permeability to calcium ion (Ca 2+ ).…”

“…Notably, it is found that their expression has been altered in IBD patients and colitis models ( Table 1), suggesting an involvement of TRP channels in IBD. In particular, IBD patients are associated with a visceral hypersensitivity (VHS), which is featured of an aberrant and chronic visceral pain (5,12). As visceral nociceptors, TRP channels are proposed to be responsible for VHS in IBD.…”

“…Visceral hyperalgesia and increased visceromotor response (VMR) were also confirmed in rats with 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis (86,87), while TRPV1 antagonist (JYL1421) could prevent and relieve the VHS (86). Additional studies exhibited that TRPV1-knockout (Trpv1 −/− ) mice conferred a resistance to colorectal distension (78,104), and VHS was enhanced by inflammatory mediators, such as bradykinin, 5-HT, histamine, and prostaglandin E2 (PGE2) in WT mice but not in Trpv1 −/− mice (12). SP was demonstrated to enhance the sensitivity and function of TRPV1 in DSS-induced colitis and in vitro (78), suggesting the engagement of neuropeptides in VHS.…”