Zsa Zsa Weerts

Chapter 1 14 One of the mechanisms at the intestinal level that is associated with IBS, in at least a subset of patients, is immune activation. Several studies have shown increased numbers of mucosal mast cells, eosinophils, and T-lymphocytes in the small and large intestine of IBS patients versus healthy controls. 18 Furthermore, the mast cells found were located more closely to nerve endings and were more often in degranulating state in IBS patients, than in controls. 18,38 This intestinal immune activation may result in increased intestinal permeability, which leads to further low-grade immune cell infiltration. 18 Peripheral pro-inflammatory chemokines, cytokines, prostaglandins, substance P, calcitonin G-related peptide (CGRP), and several neurotrophins can subsequently activate and sensitize intestinal sensory nerve endings, thereby mediating nociceptive processes. This finding has been underscored by the fact that mucosal mediators derived from biopsy supernatants of patients with IBS provoked greater activation of visceral pain pathways when applied to intestinal preparations, compared with controls. 18,38 Nociceptive neurons that play a role in the intestinal nerve sensitization associated with IBS can express Transient Receptor Potential (TRP) channels. The TRP family comprises numerous ligand-gated cation channels located in nociceptive neurons of vagal, spinal, and splanchnic primary afferents or in immune cells. 45,46 They are expressed in multiple visceral organs and have various chemo-, thermo-, and mechano-sensory functions. 47,48 Several types of TRP channels are present in the GI tract and have been implicated in visceral pain generation or inhibition, such as TRP Vanilloid 1 (TRPV1), TRP Ankyrin 1 (TRPA1), TRP Vanilloid 4 (TRPV4), and TRP Melastatin 8 (TRPM8). The most widely studied nociceptor, TRPV1, can be activated by high temperatures, low pH and exogeneous stimulants, e.g. the pungent substance in hot chili peppers (capsaicin); mustard oil; and anandamide. 48 Activation results in release of several proinflammatory neurokines such as substance P and CGRP. The role of TRPV1 modulation in sensory hyperalgesia has been established in animal models of visceral pain. 49 In addition, several studies demonstrated an increased colonic TRPV1 expression in IBS patients when compared to controls 50,51 , and elevated pain responses to capsaicin compared to controls. 52 TRPA1 is co-existing with TRPV1 on visceral afferents and likely functioning through interaction with TRPV1. 45 TRPA1 has mechano-sensory properties and in addition can be activated by low temperatures and various pungent compounds, e.g. cinnamon, garlic, and hydrogen peroxide. TRPV4 can be activated by osmosis, mechanical force, and slightly warmer temperatures than room temperature. Besides long-standing evidence from animal models that TRPA1 and TRPV4 are implicated in pain generation, a recent study has shown increased TRPA1 and TRPV4 mediated responses by neurons derived from biopsies of IBS patients, compared with healthy