17.12.8 TRPA1

TRP channel ankyrin 1 (TRPA1) has been implicated as a mechanosensor214 and a major mediator of inflammatory pain.215 In gut innervating sensory neurons, TRPA1 expression is more restricted than that observed for TRPV1. In these neurons, TRPA1 is localized in both vagal and spinal afferents, with 55% of vagal gastroesophageal afferent neurons, 54% of splanchnic colonic, and 58% of pelvic colon innervating DRG neurons expressing TRPA1.35,216 In peripheral tissue, TRPA1 is located in mucosal, serosal, and mesenteric nerve fibers,35 indicating that TRPA1 is well placed to participate in the function of these afferent subtypes. Correspondingly, TRPA1 agonists (mustard oil or cinnamaldehyde) universally evoke mechanical sensitization of serosal and mesenteric35 high-threshold63 colonic afferents and pelvic mucosal afferents.35 These compounds also activate colon innervating DRG neurons in isolation.216 The use of TRPA1−/− mice has allowed specific determination of the afferent fiber types that utilize TRPA1 to detect mechanical stimuli. These studies show striking deficits occurring in high-threshold colonic afferents, specifically splanchnic mesenteric afferents and splanchnic and pelvic serosal afferents (Fig. 17.10).35 Furthermore, TRPA1 makes a modest contribution to low-threshold mucosal afferent mechanosensitivity in both vagal and pelvic pathways innervating the esophagus/stomach and colon, respectively. In contrast, TRPA1 does not contribute to the mechanosensitivity of vagal tension receptors or pelvic muscular and muscular/mucosal afferents. Interestingly, these are the classes of afferent that are affected by TRPV1 deletion.37,194 Another important finding is the observation that TRPA1 deletion increases the activation thresholds of serosal and mesenteric afferents to mechanical stimuli,35 suggesting that TRPA1 is important in setting mechanical activation thresholds. The predominant mechanosensory role for TRPA1 in high-threshold serosal and mesenteric afferents combined with the ability of TRPA1 agonists to increase the mechanical responsiveness of these afferents is suggestive of an involvement in pain. Supporting this assertion, TRPA1−/− mice also display decreased VMR to high intensity (80 mmHg) CRD,35 but not lower distension pressures (15–60 mmHg).216 The observation that intracolonic administration of TRPA1 agonists enhances VMR to the higher distending pressures (45 and 60 mmHg) within 2 h of administration216 suggests that TRPA1 can modulate visceral mechanical hyperalgesia (discussed below). Further inference can also be deduced from the observation that the classes of TRPA1−/− afferent displaying deficits are exactly the same classes of TRPA1+/+ afferent displaying mechanical hypersensitivity after TNBS-induced colitis, namely, splanchnic mesenteric and serosal afferents and pelvic serosal and mucosal afferents.35,48,99

Mustard oil has long been used as a visceral inflammatory model to provoke tissue damage and sensitize nociceptors.197,217 We now know that mustard oil (allyl-isothiocynate) is a TRPA1 agonist,218 and recent findings provide us with a more complete understanding of how this compound causes these effects in the viscera. TRPA1 agonists induce neurogenic inflammation via the release of substance P and CGRP,219 with increases in cytokines associated with macrophage and neutrophil activation and recruitment.220 However, the contribution of TRPA1 to different types of inflammation may not be as prevalent as that of TRPV1, with recent reports suggesting that the severity of colitis induced by TNBS is unaffected by TRPA1 deletion.216