Abstract
The role of transient receptor potential vanilloid subtype 4 (TRPV4) channels in urinary bladder afferent neural pathways was investigated using spinal c-fos measurements in mice. Anesthetized wild type and TRPV4 knockout (−/−) mice underwent noxious bladder distention and treatment with either intravesical instillation with lipopolysaccharide (LPS), or the TRPV1 agonist resiniferatoxin (RTX), vehicle or an intraperitoneal injected TRPV4 antagonist (HC067047). Mice underwent paraformaldehyde perfusion for rapid fixation and L6-S1 spinal cord sections were removed followed by immunohistochemical staining for c-fos. A number of c-fos expressing neurons in the dorsal horns of L6-S1 spinal cord transections were quantified. Groups were compared using univariate ANOVA. Even with the absence of bladder inflammation on H&E, the TRPV4 −/− mice still have a significant twofold higher c-fos expression (n = 39, SD 2) after noxious bladder distention compared to wild type mice (n = 20, SD 3). A twofold increase in c-fos expression was observed after LPS treatment in wild types (n = 42, SD 5), but no increase was seen in TRPV4 −/− mice (n = 42, SD 2). After desensitization of primary afferent C-nerve fibers with RTX, c-fos expression in TRPV4−/− mice decreased significantly (threefold) (n = 12, SD 4). Results imply that TRPV4 channels are important for bladder afferent signaling. TRPV4 −/− mice bladders generate more noxious sensory output, which is predominantly mediated through TRPV1 expressing high threshold nerve fibers. This study reveals TRPV1 related adaptive changes in afferent pathways of the TRPV4 −/− mouse. We propose that this effect is caused by a congenital impairment of low threshold nerves that mediate normal bladder filling sensations.Electronic supplementary materialThe online version of this article (doi:10.1007/s00424-016-1859-9) contains supplementary material, which is available to authorized users.
Highlights
Transient receptor potential vanilloid subtype 4 (TRPV4) is a non-selective Ca2+-permeable cation channel that is located on the membranes of urinary bladder epithelial cells [9, 14, 19, 20]
The spinal c-fos in vivo model was used to investigate the role of TRPV4 channels in bladder afferent signaling during noxious stretch and bladder inflammation
Results of this study demonstrate that the TRPV4 −/− phenotype has disturbed signaling during noxious stimulation of the bladder
Summary
Transient receptor potential vanilloid subtype 4 (TRPV4) is a non-selective Ca2+-permeable cation channel that is located on the membranes of urinary bladder epithelial cells [9, 14, 19, 20]. Stretch in the urothelium causes a TRPV4 mediated Ca2+ influx into the cell which triggers the release of ATP, a potent activator of afferent nerve fibers in the bladder [8, 11, 17, 24]. These afferents contain low and high threshold nerve fibers, that mostly consist of Pflugers Arch - Eur J Physiol (2016) 468:1741–1749 myelinated Aδ fibers, and a group of silent fibers that consist of unmyelinated C-nerve fibers [11, 15, 17, 28]. The high threshold fibers express TRPV1 receptors and are important for inflammatory responses and pain [28]
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