Neurourology and Urodynamics 26:451–453 (2007)

EDITORIAL COMMENT

Re: Gevaert T et al. 2007. Neurourol Urodynam 26:424–432, Liu L et al.2007. Neurourol Urodynam 26:433–438, and Gevaert T et al. 2007.Neurourol Urodynam 26:440–450 — Functional Role of the TRPV1

Receptor in the Urinary Bladder

The target for capsaicin, the ‘‘vanilloid’’ receptor TRPV1(capsaicin receptor, previously termed vanilloid receptor type1, VR1) is a non-specific ion channel activated by capsaicin,heat, protons, and endogenous ligands, such as anandamide.1

In the lower urinary tract (LUT), it is expressed in variousstructures. In the bladder TRPV1 is known to be localized on asubpopulation of primary sensory neurons, which also aresynthesizing substance P and calcium gene-related peptide(CGRP). TRPV1-immunoreactive fibers form two distinctvaricose plexuses in the bladder: in the mucosa, and in themuscular layer, where they impinge on the surface of thesmooth muscle cells.2 However, the receptor is also expressedin non-neuronal structures, such as the urothelium,3 andinterstitial cells.4 TRPV1 receptors have also been demon-strated on detrusor myocytes.4

Despite increasing knowledge about the structure, proper-ties, and distribution of the TRPV1 receptor, its functional rolein the normal LUT has not been established. Some informationis available on its role in various LUT disorders, but detailedinformation is often lacking. Avelino and Cruz5 pointed outsome areas that have been studied, and where the TRPV1receptor may have a defined role, e.g., pain perception, controlof bladder reflex activity in pathological states, and possiblyinvolvement in cellular differentiation. Thus, many detailsconcerning the effects mediated via the TRPV1 receptors in theLUT remain to be studied and clarified.

Intravesical instillation of capsaicin was shown to havean acute excitatory effect on the responsiveness of theurinary bladder to reflex activation, and it was suggested that‘‘a capsaicin-sensitive mechanism(s) is involved in the regula-tion of micturition threshold.’’6 Clinically, the interest fortherapeutic use of intravesical capsaicin sparkled from thereport by Fowler et al.7 on the therapeutic effectiveness inpatients with neurogenic detrusor overactivity. The rationalefor the use of vanilloids (capsaicin and resiniferatoxin, RTX)was their desensitizing effect on C-fiber-afferents. TRPV1seems to be involved in the regulation of the frequency ofbladder reflex contractions, either through direct excitation ofsensory fibers or through the urothelial cell/interstitial cell/afferent fiber signaling pathway, including release of media-tors from the urothelium. However, local, non-neural effects ofvanilloids eventually influencing bladder contractility havenot been widely studied. To fill this gap in our knowledge,Gevaert et al.8 using the isolated whole rat bladder as a modelinvestigated the effects of RTX on the autonomous contrac-tility that can be demonstrated in isolated normal as well asneurogenic bladders. This approach gives an opportunity to

study non-micturition reflex mediated, functional effects ofRTX.

Female Wistar rats were made paraplegic, and betweenDays 21 and 28 after spinalization, they were treated withintravesical RTX. Three days after surgery, the bladder wasexcised and placed in a heated organ bath, where intravesicalpressures were measured. The effects of intravesical volumeload, the non-selective muscarinic agonist carbachol, andelectrical stimulation on contractile parameters were studiedin both groups. Arbitrary definitions for intravesical pressurechanges were used. Thus, ‘‘macro-transients’’ were defined aspressure changes of at least 0.5 cmH2O, lasting between 5 and30 sec and ending when the pressure level had fallen to 25% ofits original height. ‘‘Spikes’’ were defined as pressure changesof at least 0.1 cmH2O, lasting between 0 and 3 sec and endingwhen the pressure level had come back to initial baseline. Bothmacro-transients and spikes can be demonstrated in theisolated normal rat bladder.

Compared to vehicle controls, RTX reduced the duration ofmacro-transients in the normal bladder, increased theiramplitude, but did not affect their frequency. The number ofspikes was increased. In neurogenic bladders, where long-lasting macro-transients with frequent spikes were demon-strated, RTX reduced the number of macro-transients andspikes, increased the amplitude of macro-transients, andnormalized their duration. Furthermore, RTX induced anincreased sensitivity to carbachol, but qualitatively theresponses were not different from those found innormal bladders. RTX also increased the effect of electricalstimulation.

Even if it is not known what these changes induced by RTXmean for the function of the bladder in vivo, the observationsmade may support the authors’ conclusion that the effects ofRTX on autonomous bladder contractility provide evidence forlocal, non-neural effects of the drug, both in the normal andneurogenic bladder. However, it should be remembered thatthe isolated bladder is decentralized, not denervated, whichmeans that RTX could still affect remaining nerves and causerelease of various mediators. Thus, it is not certain that only

No conflict of interest reported by the author(s).*Correspondence to: K.-E. Andersson, MD, PhD, Wake Forest Institute forRegenerative Medicine, Wake Forest University School of Medicine, MedicalCenter Boulevard, Winston Salem, NC 27157 E-mail: keanders@wfubmc.eduPublished online 28 March 2007 in Wiley InterScience(www.interscience.wiley.com)DOI 10.1002/nau.20418

� 2007 Wiley-Liss, Inc.

non-neural effects have been studied. Whether or not theeffects observed can be linked to the beneficial effects of RTXon neurogenic detrusor overactivity can only be speculated on.

The exact site of action of RTX could not be established, butthe urothelium may be a reasonable target. Functional TRPV1receptors have been demonstrated on rat bladder urothelium.Furthermore, TRPV1-knockout mice exhibit diminished nitricoxide and stretch-evoked ATP release from urothelial cells.9

Thus, a urothelial site of action is probable and would be inline with the observations of Apostolidis et al.,10 who foundthat in bladder biopsies from patients with neurogenicdetrusor overactivity, there was an increased number ofurothelial TRPV1 receptors. Successful treatment with intra-vesical RTX decreased the number of these receptors.

Gevaert et al.8 suggested that the changes they observedafter RTX treatment may be explained by a facilitated signaltransduction, i.e., that the propagation of the spontaneouscontractions generated by individual ‘‘units’’ of detrusor cellsmay be facilitated, resulting in recruitment of more units. Thisseems reasonable, but the mechanism behind is unclear. Aneffect on e.g., interstitial cells contributing to the RTX changesobserved cannot be excluded, but may be difficult to prove.Again an effect on nerves or ‘‘local circuits’’11 with release ofcontractant mediators would be a possibility, as pointed outby the authors.

Gevaert et al.12 again using the isolated whole rat bladdermodel also characterized the effects of piperine on autono-mous contractile activity. Piperine is a TRPV1 receptor agonistwith a pharmacological profile similar to that of capsaicin andRTX, but with some additional, interesting properties. Impor-tantly, they also studied the role of TRPV1 in volume-inducedcontractile changes using selective (capsazepine) and non-selective (ruthenium red) TRPV1-antagonists. Inhibition ofTRPV1 with capsazepine and ruthenium red significantlyreduced the volume-evoked rise in contractile amplitude inisolated bladders, suggesting an involvement of TRPV1 in theactivity induced by stretch. This is an important observation,suggesting that TRPV1 receptors may be involved in normalbladder function, as has previously been suggested to be thecase in mice.9

The involvement of TRPV1 in the mediation of pain hasbeen widely explored, also in the LUT, and intravesicaladministration of capsaicin and RTX has been used as a painmodel.13 Maggi et al.14 instilled capsaicin intravesically topatients with hypersensitive bladder disorders and found thatall the patients reported disappearance or marked attenuationof their symptoms a few days after capsaicin application. Ifpatients with hypersensitivity disorders exhibit changes inTRPV1 mRNA expression in different regions of the bladderhas up to now not been established.

Liu et al.15 determined the expression profiles of TRPV1mRNA in different regions of human bladder and testedthe hypothesis that there would be an upregulation of TRPV1in the mucosa of patients with bladder hypersensitivity,but not idiopathic detrusor overactivity. Women withsensory urgency (SU; according to the old ICS definition),interstitial cystitis, and idiopathic detrusor overactivity weresubject to careful clinical investigation, including videouro-dynamics and cystoscopy. Cold cup biopsies were obtained,dissected into mucosa and muscle, and evaluated forTRPV1 mRNA expression using quantitative competitive RT-PCR. Age-matched control biopsies were taken from asympto-matic women. It was found that TRPV1 mRNA from SUtrigonal mucosa was significantly higher than control trigonalmucosa or SU bladder body mucosa. In contrast, in patientswith idiopathic detrusor overactivity and interstitial cystitis,

there was no difference between trigonal and body mucosa.An interesting finding was that TRPV1 mRNA expressed in SUtrigonal mucosa was significantly inversely correlated withthe bladder volume at first sensation of filling during cysto-metry. No such relationship was seen for trigonal mucosafrom patients with idiopathic detrusor overactivity, and nodifference was seen in bladder body mucosa from any diseasegroup compared to age-matched controls. Liu et al.15 con-cluded that the symptoms of SU were associated with theincreased expression of TRPV1 mRNA in the trigonal mucosa,and that TRPV1 may play a role in SU and premature firstbladder sensation on filling. This conclusion is in line with thepositive effects of capsaicin in patients with bladder hyper-sensitivity disorders reported by Maggi et al.14 It would havebeen interesting to know if treatment with vanilloidsdecreased the expression of TPRV1 in parallel with theexpected symptom improvement, similar to what Apostolidiset al.10 found in patients with neurogenic detrusor over-activity. The observation that TPRV1 may influence firstsensation of filling in SU patients raises the question whetherTRPV1 is involved in bladder sensory perception also innormal individuals. This question may be possible to answerwhen selective blockers of the TRPV1 receptor becomeavailable.16

Another interesting finding in the study by Liu et al.15 wasthe low expression of TRPV1 mRNA in interstitial cystitispatients. Whether or not this is related to methodologicaldifficulties or reflects that TRPV1 is not involved in thepathophysiology of the disorder requires further study. Theobservation is in obvious disagreement with those of Mukerjiet al.17 who found in 20 women with interstitial cystitis(painful bladder syndrome) that there was a marked increasein the suburothelial nerve fibres expressing TRPV1 comparedto normal controls, and that the density of TRPV1 receptorscorrelated with the pain score.

Our knowledge about the functional role of TRPV1receptors in the LUT, and on endogenous activators of thesereceptors, is incomplete, and further research is needed.Selective blockers of the receptor would give valuableinformation, and may also have useful therapeutic effects.16

The present ways of modulating (desensitizing) the TPRV1receptors with capsaicin and RTX have both experimental andclinical limitations. However, the TRP family seems to be wellrepresented in the bladder. Not only TRPV1, but also TRPV2,TRPV4, TRPM8, and TRPA1 have been demonstrated in theurothelium/suburothelim,18–20 and contractile mechanismscoupled to TRPA1 receptor activation have recently beenreported.18 The functional importance of TRPA1 and othermembers of the TRP family for bladder function remains to beelucidated, and the possibility that these receptors may betargets for future drugs for treatment of bladder disordersshould be further explored.

K.-E. Andersson*Wake Forest Institute for Regenerative Medicine

Wake Forest University School of MedicineWinston Salem, North Carolina

REFERENCES

1. Tominaga M, Tominaga T. Structure and function of TRPV1. Pflugers Arch2005;451:143–50.

2. Avelino A, Cruz C, Nagy I, et al. Vanilloid receptor 1 expression in the raturinary tract. Neuroscience 2002;109:787–98.

3. Birder LA, Kanai AJ, de Groat WC, et al. Vanilloid receptor expression suggestsa sensory role for urinary bladder epithelial cells. Proc Natl Acad Sci U S A2001;98:13396–401.

Neurourology and Urodynamics DOI 10.1002/nau

452 Andersson

4. Ost D, Roskams T, Van Der Aa F, et al. Topography of the vanilloid receptor inthe human bladder: More than just the nerve fibers. J Urol 2002;168:293–7.

5. Avelino A, Cruz F. TRPV1 (vanilloid receptor) in the urinary tract: Expression,function and clinical applications. Naunyn Schmiedebergs Arch Pharmacol2006;373:287–99.

6. Santicioli P, Maggi CA, Meli A. The effect of capsaicin pretreatment on thecystometrograms of urethane anesthetized rats. J Urol 1985;133:700–3.

7. Fowler CJ, Jewkes D, McDonald WI, et al. Intravesical capsaicin forneurogenic bladder dysfunction. Lancet 1992;339:1239.

8. Gevaert T, Vandepitte J, Ost D, et al. Autonomous contractile activity in theisolated rat bladder is modulated by a TRPV1 dependent mechanism.Neurourol Urodyn 2007;26:424–32.

9. Birder LA, Nakamura Y, Kiss S, et al. Altered urinary bladder function inmice lacking the vanilloid receptor TRPV1. Nat Neurosci 2002;5:856–60.

10. Apostolidis A, Brady CM, Yiangou Y, Davis J, Fowler CJ, Anand P. Capsaicinreceptor TRPV1 in urothelium of neurogenic human bladders and effect ofintravesical resiniferatoxin. Urology 2005;65:400–5.

11. Gillespie JI, Markerink-van Ittersum M, de Vente J. Sensory collaterals,intramural ganglia and motor nerves in the guinea-pig bladder: Evidence forintramural neural circuits. Cell Tissue Res 2006;325:33–45.

12. Gevaert T, Vandepitte J, Hutchings G, et al. TRPV1 is involved in stretch-evoked contractile changes in the rat autonomous bladder model: A studywith piperine, a new TRPV1 agonist. Neurourol Urodyn 2007;26:440–50.

13. Craft RM, Carlisi VJ, Mattia A, et al. Behavioral characterization of theexcitatory and desensitizing effects of intravesical capsaicin and resinifer-atoxin in the rat. Pain 1993;55:205–15.

14. Maggi CA, Barbanti G, Santicioli P, et al. Cystometric evidence that capsaicin-sensitive nerves modulate the afferent branch of micturition reflex inhumans. J Urol 1989;142:150–4.

15. Liu L, Mansfield KJ, Kristiana I, et al. The molecular basis of urgency: Regionaldifference of vanilloid receptor expression in the human urinary bladder.Neurourol Urodyn 2007;26:433–8.

16. Szallasi A. Small molecule vanilloid TRPV1 receptor antagonists approachingdrug status: Can they live up to the expectations? Naunyn SchmiedebergsArch Pharmacol 2006;373:273–86.

17. Mukerji G, Yiangou Y, Agarwal SK, et al. Transient receptor potentialvanilloid receptor subtype 1 in painful bladder syndrome and its correlationwith pain. J Urol 2006;176:797–801.

18. Andrade EL, Ferreira J, Andre E, et al. Contractile mechanisms coupled toTRPA1 receptor activation in rat urinary bladder. Biochem Pharmacol2006;72:104–14.

19. de Groat WC. Integrative control of the lower urinary tract: Preclinicalperspective. Br J Pharmacol 2006;147(Suppl 2):S25–40.

20. Mukerji G, Yiangou Y, Corcoran SL, et al. Cool and menthol receptor TRPM8 inhuman urinary bladder disorders and clinical correlations. BMC Urol2006;6:6.

Neurourology and Urodynamics DOI 10.1002/nau

TRPV1 Receptor in the Urinary Bladder 453