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TRP channels as therapeutic targets in IBS 77 4 Sensory afferents of the vagal and spinal nerves have previously been divided in different subclasses. 11 Based on their sensitivity to mechanical stimuli, afferents were divided in mucosal, muscular, serosal and mesenteric fibre classes. 2 Mucosal afferents were defined as responsive to fine tactile and chemical stimuli, whereas serosal and mesenteric afferents respond to noxious mechanical stimuli. 1 Sensing of intermediate (physiological) distension was attributed to muscular afferents. An additional class specific to the pelvic pathway, the muscular-mucosal class, responds to tactile and distension stimuli. It should be noted that evidence supporting the suspected anatomical distribution described above is currently lacking. Song et al . have attempted to morphologically identify specialised afferent axonal structures in the guinea pig intestine. 12 They were able to demonstrate mechanosensitive fibres in the mesenteries and preparations of isolated mucosa/submucosa of the ileum and colon. However, no mechanosensitive fibres were observed in preparations of isolated muscle layers (with intact myenteric ganglia and serosa). Afferent functioning therefore appears to depend on molecular characteristics rather than the location within the gut wall. 1,13 Functional differences in nociceptor transducer molecules and their divergent expression along sensory afferents determine the physiological role of these afferents. 13 Understanding the functioning of individual TRP channels may provide further insights into nociceptive processes and sensitization mechanisms. Below we will discuss in detail the TRP channels that have been identified as key players in visceral nociception. These include TRPV1, TRPV4, TRPA1 and TRPM8. An overview of current data on these channels and their implications in IBS is provided in Table 4.1 . TRP channel regulation In order to understand TRP channel functioning, one must be aware of the complex molecular modulation that these channels are subjected to. Modulatory processes can either result in sensitization or desensitization of the respective afferent. 14 While desensitization prevents nociceptive signaling, sensitization of nociceptors enhances their discharge ( i.e. potentiates the nociceptor response to a second stimulus).