Sustained TRPA1 activation in vivo

Transient receptor potential A1 (TRPA1) is a calcium permeable non-selective cation channel that is selectively localized to peptidergic C-fibres in the pain pathway. TRPA1 is highly conserved across the animal kingdom and it is able to detect a wide range of potentially toxic environmental chemicals. An unusual mechanism of TRPA1 activation was recently elucidated in which reactive agonists bind covalently to cysteines and lysine in the intracellular N-terminus. Despite a covalent activation mechanism, only transient TRPA1 activation is seen in the maintained presence of reactive agonists in whole-cell patch clamp experiments. I suggest that previous patch clamp studies are performed under conditions that do not fully mimic all aspects of TRPA1 activation. Here, I argue that compelling evidence exists for sustained TRPA1 activation in several chronic (neuropathic) pain-related pathophysiological conditions in vivo. I discuss briefly putative mechanisms that are likely to contribute to and maintain sustained TRPA1 agonist levels through increased production and/or decreased metabolism and inactivation. Chronic pain can be understood as a false alarm evoked by sustained and increased levels of endogenous TRPA1 agonists in various pathophysiological conditions.