Abstract
Both TRPV1 and P2X receptors present on bladder sensory nerve fibres have been implicated in mechanosensation during bladder filling. The aim of this study was to determine possible interactions between these receptors in modulating afferent nerve activity. In wildtype (TRPV1+/+) and TRPV1 knockout (TRPV1−/−) mice, bladder afferent nerve activity, intravesical pressure, and luminal ATP and acetylcholine levels were determined and also intracellular calcium responses of dissociated pelvic DRG neurones and primary mouse urothelial cells (PMUCs). Bladder afferent nerve responses to the purinergic agonist αβMethylene-ATP were depressed in TRPV1−/− mice (p ≤ 0.001) and also in TRPV1+/+ mice treated with the TRPV1-antagonist capsazepine (10 µM; p ≤ 0.001). These effects were independent of changes in bladder compliance or contractility. Responses of DRG neuron to αβMethylene-ATP (30 µM) were unchanged in the TRPV1−/− mice, but the proportion of responsive neurones was reduced (p ≤ 0.01). Although the TRPV1 agonist capsaicin (1 µM) did not evoke intracellular responses in PMUCs from TRPV1+/+ mice, luminal ATP levels were reduced in the TRPV1−/− mice (p ≤ 0.001) compared to wildtype. TRPV1 modulates P2X mediated afferent responses and provides a mechanistic basis for the decrease in sensory symptoms observed following resiniferatoxin and capsaicin treatment for lower urinary tract symptoms.
Highlights
As the bladder fills, the degree of distension is detected by mechanosensitive ion channels located either on sensory nerve terminals or on the specialised epithelial lining of the bladder, the urothelium
The afferent response to αβMe-ATP was significantly attenuated in TRPV1−/− mice compared to TRPV1+/+ control mice (p ≤ 0.0001, n = 9) (Fig. 2a)
The results presented in this study provide the first direct evidence that the TRPV1 receptor is able to influence bladder afferent responses to P2X stimulation, a process considered essential to mechanosensation during bladder filling
Summary
The degree of distension is detected by mechanosensitive ion channels located either on sensory nerve terminals or on the specialised epithelial lining of the bladder, the urothelium. This evokes an afferent signal that is conveyed to the CNS via the dorsal root ganglia. It has been shown that stretch or distension of the urothelium evokes the graded release of non-neuronal ATP5 which activates purinergic receptors located on the afferent terminal to control afferent firing. TRPV1 is predominantly expressed on primary sensory afferent nerve fibres, whilst contradictory evidence both support and negate a functional role for TRPV1 in the urothelium[14,15,16,17,18,19,20]
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