Vanilloid receptor TRPV1: hot on the tongue and inflaming the colon

Transient receptor potential (TRP) ion channels have become a hot spot in neurophysiology, sensory neuropharmacology and pain research. This cation channel superfamily represents an ancient sensory apparatus of the cell, responding to temperature, touch, sound, osmolarity, pheromones, taste, pain and other stimuli.1 TRP channels are essential for humans to appreciate pungent, sweet, bitter, umami and other tastes2,3 and to discriminate warmth, heat and cold.1,4 The TRP channel of the vanilloid type 1 (TRPV1) has been previously recognized as the receptor for capsaicin, the pungent ingredient in red pepper fruits of the genus Capsicum including paprika, jalapeño and cayenne, to name a few. What has made TRPV1 so interesting to pain research is its sensitivity to noxious heat, acidosis and noxious chemicals and its property to become sensitized by inflammatory and algesic mediators. TRPV1 thus behaves as a multimodal nocisensor of afferent neurones and is hypothesized to be a key player in the hyperalgesia associated with inflammation. Consequently, TRPV1 is viewed as a promising target for novel analgesics. Transient receptor potential vanilloid type 1 is present in the gastrointestinal (GI) tract where it is primarily associated with axons of spinal afferent neurones and, to some extent, vagal afferents.5–7 TRPV1-like immunoreactivity has also been found on enteric neurones and GI epithelial cells,8–10 but it is not yet known whether this molecule represents TRPV1-α or TRPV1-β. The latter is a non-functional form derived from alternative splicing of the trpv1 gene.11 There is ample evidence that the functional TRPV1-α expressed by extrinsic sensory neurones in the gut mediates the effect of capsaicin to excite afferent neurones and to give rise to abdominal pain.12 In addition to causing pain, direct administration of capsaicin into the human jejunum can elicit the sensation of warmth.13 Emerging evidence indicates that these hot spots are not only relevant to perception but may also set the intestine ‘on fire’ because of immunological effects. In this issue, Kimball et al.14 report that a novel TRPV1 channel blocker, JNJ 10185734, reduces the severity of dextran sulphate sodium (DSS)-induced colitis in mice. This finding implies that TRPV1 contributes to the initiation or maintenance of inflammatory processes in the gut. Seen in context with related observations, the report by Kimball et al.14 is intriguing in several aspects. Most remarkable is the emerging concept that TRPV1 participates in GI inflammation, as shown in a number of experimental models including colitis induced by DSS14–16 and ileitis induced by Clostridium difficile toxin A17 or anandamide.18 The attenuation of colitis by JNJ 10185734 is shared by another TRPV1 channel blocker, capsazepine,14,15 and reproduced by genetic deletion of TRPV1.16 Kimball et al.14 showed that, during the 7-day treatment with DSS, JNJ 10185734 (0.5–5 mg kg−1) given orally and capsazepine (2 mg kg−1) administered intraperitoneally reduced colonic injury and dysfunction to a comparable degree. How do DSS and C. difficile toxin A involve TRPV1 in causing GI inflammation? Preliminary evidence suggests that, in both models, TRPV1 expressed by extrinsic sensory neurones provides a link between the experimental stimulus and the ensuing inflammatory process. The involvement of neurones in C. difficile toxin A-induced inflammation and diarrhoea is well characterized.17Clostridium difficile toxin A may activate sequentially endovanilloids such as anandamide, TRPV1,18 sensory nerve terminals in the mucosa, with release of substance P, enteric neurones and immune cells and, ultimately, hypersecretion, inflammation and mucosal damage.17,18 How DSS utilizes neural TRPV1 to induce colitis is less understood. Given that DSS is thought to be a relevant model for certain aspects of inflammatory bowel disease (IBD), the experimental findings obtained with capsazepine and JNJ 10185734 suggest that TRPV1 may contribute to IBD. Although there is no proof of this concept, it is important to note that IBD is associated with upregulation of TRPV1 in nerve fibres of the colon.19 Similarly, experimentally induced gastric acid injury7 and inflammation of the skin20 lead to upregulation of TRPV1 in spinal afferent neurones, a process in which neurotrophic factors seem to play a crucial role.21 These observations warrant further investigation of the role of TRPV1 in IBD and in experimental models of colitis. As pointed out by Kimball et al.14 attenuation of DSS-induced colitis by TRPV1 channel blockers highlights the role of neurogenic mechanisms in GI inflammation and may herald the advent of a new class of drugs in the treatment of IBD. The development of JNJ 10185734 as a TRPV1 channel blocker14 also demonstrates that small molecular weight non-vanilloid TRPV1 channel blockers with oral bioavailability can be designed. Previously, capsazepine was considered a reference TRPV1 antagonist, although its selectivity for TRPV1 is rather poor.14,22 To understand the role of TRPV1 in health and disease, it is important to evaluate more selective blockers of TRPV1. The full pharmacological activity profile of JNJ 10185734 is unavailable and it is particularly difficult to assess the significance of the bell-shaped dose–response curve for the effect of JNJ 10185734 to reduce DSS-induced colitis14. As discussed by the authors14 this feature of JNJ 10185734 may reflect pharmacodynamic or pharmacokinetic peculiarities of the compound. It may, however, also point to the fact that TRPV1 may play proinflammatory as well as protective roles in the GI tract.12,23 In order to decipher the possible dual effects of TRPV1 in GI mucosal homeostasis, a full range of doses of the TRPV1 channel blocker need to be tested against different grades of colitis severity. The protective function of TRPV1 may result from a role of nociceptive afferent neurones which survey the integrity of the gut and activate mechanisms of protection in the face of impending injury.24 Thus, TRPV1 enhances blood flow, bicarbonate and mucus secretion in the gastroduodenal region and thereby to strengthen mucosal resistance to injury.10, 12, 23, 25–28 This protective role contrasts with the potential of TRPV1 in experimentally induced pancreatitis 29 and enteritis.14–18 Thus, blockade of TRPV1 could interfere with the function of sensory neurones resulting in increased vulnerability of the GI mucosa and tissues outside the GI tract. Unforeseen side-effects could result from the uncritical use of TRPV1 channel blockers.30 For example, taste sensations on the tongue may be disturbed.31 The challenge, therefore, is to identify whether TRPV1 channels involved in GI mucosal protection (‘good’ effects) can pharmacologically be differentiated from TRPV1 channels mediating GI inflammation and hyperalgesia (‘bad’ effects). If this issue can be resolved satisfactorily, TRPV1 channel blockers may be of substantial value in suppressing GI inflammation and pain that arise from upregulation and/or sensitization of TRPV1 in the gut.