TRPA1 receptor modulation attenuates bladder overactivity induced by spinal cord injuryc

The ankyrin-repeat transient receptor potential 1 (TRPA1) has been implicated in pathological conditions of the bladder, but its role in overactive bladder (OAB) following spinal cord injury (SCI) remains unknown. In this study, using a rat SCI model, we assessed the relevance of TRPA1 in OAB induced by SCI. SCI resulted in tissue damage, inflammation, and changes in bladder contractility and in voiding behavior. Moreover, SCI caused upregulation of TRPA1 protein and mRNA levels, in bladder and in dorsal root ganglion (DRG; L6-S1), but not in corresponding segment of spinal cord. Alteration in bladder contractility following SCI was evidenced by enhancement in cinnamaldehyde-, capsaicin-, or carbachol-induced bladder contraction as well as in its spontaneous phasic activity. Of relevance to voiding behavior, SCI induced increase in the number of nonvoiding contractions (NVCs), an important parameter associated with the OAB etiology, besides alterations in other urodynamic parameters. HC-030031 (TRPA1 antagonist) treatment decreased the number and the amplitude of NVCs while the TRPA1 antisense oligodeoxynucleotide (AS-ODN) treatment normalized the spontaneous phasic activity, decreased the cinnamaldehyde-induced bladder contraction and the number of NVCs in SCI rats. In addition, the cinnamaldehyde-induced bladder contraction was reduced by exposure of the bladder preparations to HC-030031. The efficacy of TRPA1 AS-ODN treatment was confirmed by means of the reduction of TRPA1 expression in the DRG, in the corresponding segment of the spinal cord and in the bladder, specifically in detrusor muscle. The present data show that the TRPA1 activation and upregulation seem to exert an important role in OAB following SCI. cinnamaldehyde capsaicin HC-030031 TRPA1 antisense oligodeoxynucleotide rat spinal cord injury (SCI) impairs micturition by interrupting the communication between the cerebral and spinal circuits that coordinate bladder and urethra activities (38, 39). After a period of bladder areflexia, spontaneous and involuntary bladder contractions, which characterize the overactive bladder (OAB), are triggered by the emergence of a micturition reflex at the spinal level. Concomitantly to OAB, bladder-sphincter dyssynergia is induced, resulting in inefficient voiding (11). The reorganization of bladder reflex pathways seems to be mediated, in part, by bladder afferents C-fibers (12). Therefore, the suppression of bladder afferent nerves hyperexcitability is hypothesized to be effective in OAB symptoms improvement. Studies have been carried out to identify the mechanisms that control bladder afferent activity. Several receptors have been identified in neuronal and nonneuronal structures of the bladder as potential candidate molecules in the modulation of its sensorial function, among them is the transient receptor potential vanilloid 1 (TRPV1). TRPV1 is a nonspecific ion channel activated by heat, protons (33), and vanilloids such as capsaicin and endovanilloids such as anandamide (43). The expression of TRPV1 is firmly established in sensory fibers of the bladder (3-5, 7, 8, 42). Moreover, some studies suggest that TRPV1 is also localized in structures nonneuronal of the bladder, such as urothelium (3, 4, 7, 10, 20), smooth muscle, and interstitial cells (24). Nevertheless, the localization of TRPV1 in nonneuronal cells of the bladder is still unclear due to the controversial findings that do not show the presence of TRPV1 in bladder urothelium (37, 42). Reinforcing this disagreement, a nonspecific cellular TRPV1 immunoreactivity in urothelium from TRPV1 knockout mice was observed (15). Therefore, the literature data might be interpreted carefully, taking account the antibody, species, and technique used in the study. The possible presence of TRPV1 in urothelium is of particular interest since that this tissue exhibits specialized sensory and signaling properties (7). The increase of TRPV1 expression is associated with upregulation of the urothelial functions, such as enhanced release of chemical mediators and neurotransmitters, which have been suggested to influence afferent nerve activity and to contribute to OAB symptoms (40). Intravesical administration of the TRPV1 activators, namely capsaicin or resiniferatoxin, which desensitize afferent neurons, has been introduced into clinical practice for OAB treatment. treatments significantly improved the volume parameters such as VV, RV, BC, and VE. These findings suggest that TRPA1 seems do not exert effect on the activity of spinal motor neurons responsible by control of external urethral sphincter. In summary, our in vitro and in vivo data provide strong evidences for an important role played by TRPA1 in OAB caused by SCI in rats. Thus, TRPA1 might constitute an attractive and potential target to develop a new therapy for OAB.