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TRP channels as therapeutic targets in IBS 95 4 other TRPA1 antagonists have entered the phase of testing in clinical trials. 105 Although the true potential of these drugs will need to be explored, their safety profile appears to be more favourable than that of early TRPV1 antagonists. Given this advantage, we expect a boost in TRPA1 targeted therapy development in the near future. New targets may continue to be identified. TRP channel regulatory processes in IBS constitute relatively unexplored terrain (see “TRP channel regulation”). Improved understanding of the underlying molecular processes may help identify targets that modulate TRP channel functioning. Challenges of TRP channel targeted therapy Although the possibilities of TRP channel targeted therapy appear endless, treatment development has been plagued by many challenges over the past years. 16 As mentioned above, the first TRPV1 antagonists were associated with thermo-regulatory side effects. To date, the mechanisms by which these side effects arise are unknown. New selective agents may provide a solution to this issue. However, other challenges are to be expected. 16 This is mainly provoked by two factors. First, TRP channels are expressed in a wide range of tissues (see section “Non-neuronal TRP channel expression”). Targeting TRP channels consequently affects systems other than nociceptors. For example, a systemically administered TRPV4 agonist resulted in endothelial dysfunction and cardiovascular collapse in one study. 106 TRPV1 expressed in the central nervous system is thought to have a role in mood disorders. Although conflicting data exists, TRPV1 antagonism may exacerbate depressive symptoms. 38 Regulatory relations between organ systems further complicate the matter. TRPV1-expressing neurons are thought to regulate immunological functions, and interference with this function could prove detrimental in systemic inflammatory conditions. 107 The other major issue of TRP targeted treatment development is related to the large diversity of possible stimuli of each channel. Even selective agents will not immediately overcome this hurdle. For example, a new TRPV1 antagonist that does not cause hyperthermia, was shown to potentiate proton-induced calcium influx in one study. 108 This unforeseen effect could prove problematic in the upper gastrointestinal tract, as it may result in excessive TRPV1 activation by gastric acid ( e.g . physiological gastro-oesophageal reflux). In addition, several limitations currently exist in the study of TRP channels and their role in nociception. Basic research is complicated by the lack of quality reagents. Antibodies used to investigate expression patterns possess poor specificity. A similar issue is encountered with agonists/antagonists used to investigate TRP channel functioning, which presents a major problem in understanding TRP biology. 109 Furthermore, studies