TRPV1 (vanilloid receptor) in the urinary tract: expression, function and clinical applications

REVIEW

TRPV1 (vanilloid receptor) in the urinary tract: expression,function and clinical applications

António Avelino & Francisco Cruz

Received: 9 February 2006 /Accepted: 10 April 2006 /Published online: 24 May 2006# Springer-Verlag 2006

Abstract The transient receptor potential vanilloid subfamily1 (TRPV1) is an ion channel activated by capsaicin, heat,protons and endogenous ligands such as anandamide. It islargely expressed in the urinary tract of mammals. Structuresin which the receptor expression is firmly established includesensory fibers and urothelial cells, although the presence ofTRPV1 in other cell types has been reported. As in othersystems, pain perception was the first role attributed toTRPV1 in the urinary tract. However, it is now increasinglyclear that TRPV1 also regulates the frequency of bladderreflex contractions, either through direct excitation of sensoryfibers or through urothelial-sensory fiber cross talk involvingthe release of neuromediators from the epithelial cells. Inaddition, the recent identification of the receptor in urothelialand prostatic cancer cells raise the exciting hypothesis thatTRPV1 is involved in cell differentiation. Desensitization ofthe receptor by capsaicin and resiniferatoxin has beeninvestigated for therapeutic purposes. For the moment, lowerurinary tract dysfunctions in which some benefit was obtainedinclude painful bladder syndrome and overactive bladder ofneurogenic and non-neurogenic origin. However, desensiti-

zation may become obsolete when non-toxic, potent TRPV1antagonists become available.

Keywords Urinary tract . Bladder . TRPV1 . Vanilloidreceptor . Anandamide . Resiniferatoxin . Capsaicin

Introduction

The discovery of specific binding sites for capsaicin inseveral tissues and organs, including the rat urinary bladder(Szallasi et al. 1993), initiated a rush that ended up with thecloning of the vanilloid receptor (Caterina et al. 1997),presently known as TRPV1 (transient receptor potentialvanilloid subfamily 1). In the lower urinary tract, TRPV1expression is now firmly documented not only in a largesubpopulation of nerve fibers but also in non-neuronaltissues. Knowledge about the presumable function ofTRPV1 also evolved rapidly. From a receptor initially con-sidered as an integrator of thermal and chemical noxiousstimuli, TRPV1 is emerging as a possible regulator ofbladder reflex activity and cell differentiation. These find-ings, together with the promising clinical applications ofTRPV1 targeting in the lower urinary tract, justify a reviewof the most relevant data concerning the distribution,function in the normal and pathological bladder, and resultsof TRPV1 desensitization by intravesical capsaicin orresiniferatoxin administration.

TRPV1 (formerly known as vanilloid receptor type 1) is anon-specific ion channel activated by temperatures above43°C (Caterina et al. 1997). Acidic conditions decrease itsthreshold to normal body temperature or even below it(Jordt et al. 2000; McLatchie and Bevan 2001, Tominaga etal. 1998). The molecular architecture and the identity ofagonists and antagonists of TRPV have been the object of

Naunyn-Schmiedeberg’s Arch Pharmacol (2006) 373:287–299DOI 10.1007/s00210-006-0073-2

A. Avelino : F. CruzInstitute of Histology and Embryology,Faculty of Medicine of Porto,Alameda Hernani Monteiro,4200-319 Porto, Portugal

A. Avelino : F. CruzIBMC, University of Porto,R. Campo Alegre, 823,4150-180 Porto, Portugal

F. Cruz (*)Department of Urology,Hospital São João and Faculty of Medicine of Porto,4200-076 Porto, Portugale-mail: [email protected]

several extensive reviews (Cortright and Szallasi 2004;Nagy et al. 2004, Szallasi 2006). For the purpose of thepresent one, it is enough to mention that TRPV1 belongs tothe TRP superfamily of ion channels and that it isfunctionally included in the “thermo-TRP” class. So far,four heat-sensitive ion channels including TRPV1, TRPV2,TRPV3 and TRPV4, and two cold-sensitive ion channels,TRPM8 (also called cold menthol receptor, CMR1) andTRPA1, have been identified (Caterina et al. 1997, 1999;Gudermann and Flockerzi 2005; Güler et al. 2002;McKemy et al. 2002; Peier et al. 2002; Smith et al. 2002;Story et al. 2003; Xu et al. 2002). In addition, two thermal-insensitive calcium channels, TRPV5 and TRPV6, wererecently added to the family (Van Abel et al. 2005). Itshould, nevertheless, be emphasized that although theTRPV family includes the word Bvanilloid”, only TRPV1is sensitive to vanilloid compounds. We refer the interestedreader to an in-depth review of TRPV channels publishedrecently in this journal (Niemeyer 2005).

Like many other receptors in the history of pharmacology,the triggering event in the identification of TRPV1 was thediscovery of exogenous ligands, in this case capsaicinextracted from hot peppers (Nelson 1919). Since the cloningof TRPV1, accumulating evidence suggests, however, thatendogenous ligands, as expected, do exist (Van Der Steltand Di Marzo 2004) and have already been identified in thelower urinary tract, as will be discussed later.

TRPV1 expression in sensory fibers innervatingthe urinary tract

The presence of the vanilloid receptor in the urinary tract wasdetected for the first time using radioactive resiniferatoxinbinding in the urinary bladder (Acs et al. 1994; Szallasi et al.1993) and urethra (Parlani et al. 1993) of the rat. Followingthe development of suitable antibodies, exhaustive immuno-histochemical studies in rodents showed the presence ofTRPV1 immunoreactive (IR) nerve fibers throughout theentire urinary tract, with the exception of the kidneyparenchyma (Avelino et al. 2002b; Birder et al. 2001;Tominaga et al. 1998). TRPV1-IR fibers formed two distinctvaricose plexuses in the bladder. In the mucosa, most fiberswere in close proximity to the basal cells of the transitionalepithelium, but also penetrated it up to its surface (Fig. 1a,b).In the muscular layer, TRPV1-IR fibers impinged on thesurface of the smooth muscle cells (Fig. 1c,d). Similar net-works occurred in the mucosa and in the muscular layer ofthe renal pelvis, ureter and proximal urethra. In the distalurethra, TRPV1-IR fibers were present only beneath theepithelial cells. Under the electron microscope, TRPV1 fi-bers were visible among urothelial cells (Fig. 2a) andencroached in shallow grooves on the smooth muscle cellsurface, separated by a narrow, empty cleft (Fig. 2b),

Fig. 1 TRPV1-IR fibers in the rat bladder. a Two distinct varicoseplexuses are visible, one more dense in the muscular layer and anothermore loose in the mucosa. b Some IR- fibers penetrate the epitheliallayer. c, d Higher magnification of smooth muscle cells in longitudinal(c) or transverse (d) section showing numerous immunoreactivevaricosities intimately apposed to their surface. Reproduced fromAvelino et al. 2002b

Fig. 2 Electron microscope images of TRPV1-IR fibers in the ratbladder. a intra-epithelial nerve fiber. b TRPV1-IR fiber encroachedon shallow groove of a non-labelled smooth muscle cell. Reproducedfrom Avelino et al. 2002b

288 Naunyn-Schmiedeberg’s Arch Pharmacol (2006) 373:287–299

(Avelino et al. 2002b). Immunoreaction occurred in the cellmembrane, synaptic vesicles, neurofilaments and mitochon-dria of nerve fibers and it was absent from smooth musclecells (Fig. 1d), (Avelino et al. 2002b). Interestingly, recentstudies have confirmed the occurrence of TRPV1 in synapticvesicles and demonstrated PKC dependent trafficking of thechannel from the synaptic vesicles to the cell membrane(Morenilla-Palao et al. 2004). TRPV1 was co-expressed withvesicular SNARE proteins (Morenilla-Palao et al. 2004), afinding that can explain the reduction of TRPV1 in bladdernerve fibers after botulinum toxin application (Apostolidis etal. 2005b), a well known inhibitor of SNARE activity.

In the rat bladder, the majority of TRPV1 fibers co-expressed the neuropeptides substance P (SP) and calcito-nin-gene related peptide (CGRP) (Avelino et al. 2002b).The existence of non-peptidergic, TRPV1-positive fibers isat present more controversial. Avelino et al. (2002b) couldnot detect them in the bladder. In contrast, others (Hwang etal. 2000; Wang et al. 1998) reported isolectin B4 (IB4)positive dorsal root ganglion cells innervating the rat urinarybladder. This issue needs further clarification, since peptider-gic and IB4-binding primary afferents are generally consid-ered as distinct subsets of sensory neurones with diversefunctional properties (Liu et al. 2004; Snider and Mcmahon1998, Stucky and Lewin 1999). Additionally, in the ratbladder TRPV1 also co-localizes with protease activatedreceptors (PARs) (Dattilio and Vizzard 2005). This findingmay be of crucial importance for bladder reflex controlduring inflammation, since PAR activation was shown tocontract rat urinary bladder by stimulating the release ofprostaglandins from the mucosa (Nakahara et al. 2004) andby sensitizing TRPV1 (Amadesi et al. 2004, Dai et al. 2004).

In the human urinary bladder, TRPV1-IR was detected innerve fibers coursing in the suburothelial connective tissueand in the muscular layer (Fig. 3) (Apostolidis et al. 2005b;Brady et al. 2004a; Lazzeri et al. 2004; Yiangou et al.2001). As in rodents, TRPV1-expressing fibers were alsofound among urothelial cells (Lazzeri et al. 2004). In thehuman prostatic urethra, TRPV1-IR nerve fibers formed asubepithelial varicose network from which they penetratedthe epithelial layer up to the lumen (Fig. 4), (Dinis et al.2005). TRPV1-IR nerve fibers were also present in otherareas of the gland, including the verumontanum, ejaculato-ry ducts and peri-urethral prostatic acini (Dinis et al. 2005).The most peripheral areas of the gland were devoid ofTRPV1 immunoreactivity (Dinis et al. 2005). No co-lo-calization studies have been carried out in the human uri-nary tract so far. However, as TRPV1 and P2X3-IR nervefibers were shown to disappear from the nerve fiberscoursing in the bladder wall after intravesical resinifera-

Fig. 3 TRPV1-IR fibers in the human urinary bladder. A suburothe-lium. b muscular layer. Arrows indicate fibers. Reproduced fromYiangou et al. 2001

Fig. 4 TRPV1-IR fibers in the human prostate. a Prostatic urethra. b ejaculatory duct. Reproduced from Dinis et al. 2005

Naunyn-Schmiedeberg’s Arch Pharmacol (2006) 373:287–299 289

toxin application (Brady et al. 2004a,b), the co-localizationof these two receptors is likely to occur.

TRPV1 expression in non-neuronal structuresof the urinary tract

The concept that TRPV1 expression was restricted to sen-sory fibers was irrefutably changed following the indisput-able demonstration of TRPV1 in urothelial cells of rodents,

either by RT-PCR or immunolabelling (Fig. 5) (Birder et al.2001). The latter was found in basal, intermediate and largesuperficial, umbrella cells. As in nerve fibers, the receptorwas shown to be functional. Capsaicin increased cytosolic-free calcium and nitric oxide release in urothelial cells fromTRPV1+/+ mice but not from TRPV1 –/– mice (Birder etal. 2001). This is a curious finding, since nitric oxidedecreases rather than increases bladder reflex activity(Pandita et al. 2000). In addition, in contrast with neuronalcells, TRPV1 desensitization could not be induced inurothelial cells by capsaicin or RTX application (Birder etal. 2001). No explanation for this difference has beenoffered until now.

The first report on the expression of TRPV1 in humanurothelial cells appeared in an abstract presented to the2001 meeting of the American Urological Association (Kimet al. 2001). However, 3 years went by until a full paperreported TRPV1 immunoreactivity in human urothelialcells (Lazzeri et al. 2004, Fig. 6). The TRPV1 stainingreported in this (Lazzeri et al. 2004) and subsequent reports(Apostolidis et al. 2005a,b) was not described by others(Dinis et al. 2005). Nevertheless, recent findings from ourown group seem to confirm the presence of TRPV1 inhuman urothelial cells. RT-PCR studies showed TRPV1mRNA expression in human urothelial cells, either freshlyisolated or grown in culture (Charrua and Avelino,unpublished data). Surprisingly, and in contrast to dorsal

Fig. 5 Confocal image of rat bladder urothelium stained for TRPV1(red) and cytokeratin (green) showing diffuse staining in apical cells(arrows). Reproduced from Birder et al. 2001

Fig. 6 TRPV1 immunoreactivity in nerve fibers and urothelial cells ofthe human urinary bladder. a nerve fibers in the muscle coat. b nervefibers in an unmyelinated nerve bundle. c subepithelial nerve endings

(arrows). The urothelial cells are also labelled. d intraepithelial nerveendings (arrows) and urothelial cells. Reproduced from Lazzeri et al.2004


root ganglion cells in culture (Bevan and Winter 1995;Winter et al. 1988), TRPV1 mRNA expression in urothelialcells seemed to be independent of the presence of nervegrowth factor (NGF) in the growth medium. Two otherfindings are worth mentioning. First, the TRPV1 mRNAexpression more than triplicated when the human urothelialcells were grown in the presence of inflammatory mediatorslike bradykinin, histamine, prostaglandins and serotonin(Charrua and Avelino, unpublished data). Second, cobaltuptake could be induced by capsaicin in human urothelialcells through a mechanism that could be inhibited bycapsazepine (Charrua, Nagy and Avelino, unpublisheddata), suggesting that the receptor is functional.

The primary stimulus for TRPV1 activation in urothelialcells is unknown. However, in contrast with neuronal cells,protons alone seem an unlikely stimulus, taking inconsideration the acid pH of normal urine. Nevertheless, itcan be speculated that TRPV1 becomes activated in thecontext of bladder inflammation and therefore moresensitive to acid urine, a factor that would lead to increasedreflex activity of the organ.

Very recently, functional TRPV1 receptors were reportedin human epithelial prostate cells. In fact, capsaicin and RTXwere shown to induce a concentration dependent calciuminflow in those cells that was reversed by capsazepine(Sanchez et al. 2005). In addition, TRPV1 immunoreactivitywas reported in interstitial cells of the human bladder (Ostet al. 2002) and prostate (Van der Aa et al. 2003). Thesecells, which were first identified by Cajal in the gut, form asuburothelial network that may contribute to a fast spreadof neuronal-induced smooth muscle contractions (Sui et al.2004). The presence of TRPV1-IR in interstitial cellsshould, however, be interpreted with caution, since theantibodies used were raised against the vanilloid receptor-like 1 (VRL1). This receptor, which is now known asTRPV2, shares only 55% homology with TRPV1 (Caterinaet al. 1999), and although heat sensitive, is not responsiveto capsaicin (Caterina et al. 1999).

TRPV1 immunoreactivity was also reported in smoothmuscle cells from the human bladder and in the endotheliumof capillaries and arteries but not of veins and lymphatics(Lazzeri et al. 2004; Ost et al. 2002). In addition mast cellspresent in the human bladder were also reported as immu-noreactive by one study (Lazzeri et al. 2004). These data aresurprising if one takes in consideration that studies carriedout in rodents using electronic (Avelino et al. 2002a,b, seealso Fig. 2b) and confocal microscopy (Birder et al. 2001)were unable to demonstrate such a ubiquitous distribution ofthe receptor. If the immunolabelling is specific, the func-tional meaning of TRPV1 in smooth muscle and endothelialcells is completely unclear at the moment. In mast cellsobtained from bone marrow, calcium uptake was shown tooccur after capsaicin and RTX stimulation (Biro et al. 1998).

Although it is tempting to relate these observations with theinflammatory response, capsaicin or RTX could not inducedegranulation of mast cells (Biro et al. 1998).

TRPV1 mRNA was found recently in the human uro-genital tract (Stein et al. 2004). Positive structures includedthe testis, the seminiferous tubules, the corpus cavernosum,the glans penis and its overlying skin and the scrotal skin.However, since mRNA was extracted from whole tissuehomogenates, a detailed identification of TRPV1 contain-ing structures could not be provided (Stein et al. 2004).

TRPV1 expression after intravesical applicationof capsaicin or RTX

Intravesical application of capsaicin or RTX induced a rapidand marked reduction in the density of TRPV1-IR fiberscoursing in the mucosa or in the muscular layer of the raturinary bladder (Avelino et al. 2002b). This reduction, al-though exceeding 80% at 24 h, was transient, as the numberof TRPV1-IR fibers returned to normal after 1 month(Avelino et al. 2002b). Similar changes have been reportedin the human bladder. After intravesical RTX application inpatients with neurogenic detrusor overactivity, TRPV1-IRdecreased or disappeared from suburothelial nerve fibers(Brady et al. 2004a) and from urothelial cells (Apostolidiset al. 2005a).

Intravesical capsaicin or RTX induces other profoundmodifications in TRPV1 expressing fibers. SP- and CGRP-IRvanished from the rat urinary bladder for 2 months afterintravesical application of those compounds (Avelino andCruz 2000). In addition, the expression of the peptide ga-lanin in bladder sensory neurons, usually low under normalcircumstances, increased (Avelino et al. 2002a). Galaninchanges lasted 1 month and were accompanied by the over-expression of the immediate early gene c-jun (Avelino et al.2002a). Interestingly, galanin and c-jun overexpression couldbe prevented by systemic NGF administration (Avelino et al.2002a). This suggests that a reduced retrograde transport ofneurotrophic factors may be a putative mechanism for atleast some of the neuroplastic changes detected in bladdersensory neurons after intravesical vanilloids.

Alterations seen in bladder afferents after intravesicalvanilloids application partially mimic those seen in sensoryfibers after peripheral axotomy (Zigmond et al. 1996) and canbe tentatively attributed to the degeneration of the peripheralsensory endings. In support of this concept, it should beremembered that systemic capsaicin induces degeneration ofperipheral nerve fibers in the urinary tract (Chung et al.1985). In addition, capsaicin decreases nerve fiber immuno-reactivity for PGP 9.5 (Dasgupta et al. 2000; Simone et al.1998). However, an electron microscope study of rat blad-ders subjected to topical treatment with capsaicin or RTX inconcentrations used clinically could not detect degenerated


nerve fibers at the moment of maximal TRPV1 or neuro-peptide depletion (Avelino and Cruz 2000) suggesting thatthe reduction of nerve fiber immunoreactivity should not betaken as a direct sign of degeneration. In support of thishypothesis, it may be recalled that RTX, when applied tocells transfected with TRPV1, induces rapid cell membraneloss (Caudle et al. 2003) which may contribute to a reductionin cell membrane immunoreactivity.

Role of TRPV1 in the lower urinary tract function

The role of TRPV1 to bladder function has been mostlyinferred from the effect of desensitisation of bladder sensoryfibers by capsaicin or RTX. Capsaicin-sensitive bladder af-ferents contribute to pain (Vizzard 2000a; Dinis et al. 2004a)and to bladder overactivity accompanying cystitis (Dinis etal. 2004a; Sculptoreanu et al. 2005a) or spinal transection(De Groat 1997). Intravesical capsaicin or RTX, however,cause such profound changes in the neurotransmitter contentand receptor expression of capsaicin-sensitive bladder sen-sory fibers (see above) that the role of TRPV1 could not befully appreciated. The clarification of this issue was thereforepursued in experiments making use of specific receptorantagonists and TRPV1 knock-out animals.

At the moment, it seems reasonable to accept that TRPV1regulates the frequency of bladder reflex contractions inchronically inflamed rat urinary bladders. Capsazepinedecreased the frequency of reflex contractions in cyclophos-phamide inflamed rat urinary bladders (Dinis et al. 2004b).In addition, after bladder inflammation with acetic acid orE. coli lipopolysaccharide (LPS), the frequency of bladderreflex contractions strongly increased in TRPV1 +/+, butnot in TRPV1 −/− mice (Silva et al. 2004, Charrua andAvelino, unpublished observations). In addition, it seemsalso probable that TRPV1 is involved in cystitis-inducedpain. Bladder distension at physiological levels of LPS in-flamed mice bladders increased the expression of the pain-evoked c-fos gene in sacral spinal cord neurons of TRPV1+/+ but not in TRPV1 −/− animals (Silva et al. 2004;Charrua and Avelino, unpublished observations). Thesedata are not a total surprise if one takes into accountexperimental data suggesting an intense cross-talk betweenTRPV1 and inflammation. Cystitis increases endogenousTRPV1 ligands (see below). Also, the number of bladdersensory neurons that express TRPV1 doubles after chronicbladder inflammation with cyclophosphamide (Avelino,unpublished observations). This may be related to the highlevels of neurotrophic factors produced by chronically in-flamed bladders (Bjorling et al. 2001; Guerios et al. 2006;Vizzard 2000b). NGF enhances TRPV1 translation (Ji et al.2002) and releases TRPV1 from the inhibitory control ofphosphatidylinositol-4,5-bisphosphate (Chuang et al. 2001).In addition, protein kinase A (PKA) (De Petrocellis et al.

2001), protein kinase C (PKC) (Cesare et al. 1999;Premkumar and Ahern 2000) and Ca2+/calmodulin-depen-dent kinase II (CaMkII) (Jung et al. 2004) activation byinflammatory mediators may increase TRPV1 activity byphosphorylation. It should also be mentioned that theincrease of PARs 2–4 recently detected in TRPV1 express-ing fibers and urothelial cells of inflamed bladders (Dattilioand Vizzard 2005) may contribute to sensitize TRPV1through PKC-mediated phosphorylation (Amadesi et al.2004; Dai et al. 2004). Furthermore, studies performed inprimary afferent neurons of cats suffering from felineinterstitial cystitis suggested that the sustained, slow de-sensitizing responses detected upon capsaicin applicationwere due to an enhanced activity/expression of PKC(Sculptoreanu et al. 2005b).

The role of TRPV1 in the activity of normal bladderfunction is more controversial. Capsazepine, even in veryhigh concentrations, had no effect on bladder reflex activityof normal bladders (Dinis et al. 2004b). Accordingly, thefrequency of reflex bladder contractions of TRPV1 +/+ andTRPV1 −/− mice was exactly the same (Silva et al. 2004;Charrua and Avelino, unpublished observations). Thesedata differ, however, from those of Birder et al. (2002), whoconcluded that the elimination of the TRPV1 gene increasebladder capacity and the frequency of non-voiding bladdercontractions and of low volume micturictions. It is unclearat this moment the reason why these studies differ.

The effect of TRPV1 on bladder reflex activity of in-flamed and eventually intact bladders raises the fascinatinghypothesis that the receptor, either directly or indirectly,encodes for intravesical pressure or the degree of bladderwall distension. Interestingly, the involvement of TRPV1 inmechanosensitivity was also suggested in the colon. TRPV1−/− mice were shown to be significantly less sensitive todistension than TRPV1 +/+ mice (Jones et al. 2005). Thesame was observed in TRPV1 +/+ mice pretreated withcapsazepine (Jones et al. 2005). These findings were asso-ciated with a reduction in afferent fiber sensitivity to cir-cumferential stretch of the colon (Jones et al. 2005). Whythis occurs is still unclear, but heterodimerization of TRPV1is an appealing hypothesis. Co-assembly between sub-unitsbelonging to different members of the TRP family is aknown phenomenon (Hellwig et al. 2005; Liapi and Wood2005; Rutter et al. 2005). If this happens between TRPV1and TRPV4, that exhibits mechanosensitive properties(Liedtke 2005; Suzuki et al. 2003), an explanation for theinfluence of TRPV1 on mechanosensitivity could be given.However, at this moment this hypothesis has no experi-mental support.

As stated above, TRPV1 expressing nerve fibers are par-ticularly abundant in the human prostate (Dinis et al. 2005).Taking in account the role of TRPV1 in pain perception, itis tempting to relate these fibers with pain reported by


patients with chronic pelvic pain syndrome (CPPS). TRPV1activation in the human lower urinary tract generates aburning pain sensation (Maggi et al. 1989), therefore simi-lar to that reported by CPPS patients at micturition andejaculation (Litwin et al. 1999). In addition, CPPS patientshave increased heat sensitivity in the perineal area (Yang etal. 2003). Several factors may concur to TRPV1 activationin CPPS patients. The pH of the prostate gland is muchlower than that of other human tissues (White 1975). NGFis increased in the semen of CPPS patients (Miller et al.2002). Finally, alcohol was recognized as a TRPV1 agonist(Trevisani et al. 2002) and ingestion of alcoholic beveragesenhances pain sensation in CPPS patients (Litwin et al.1999).

TRPV1 expressed in sensory nerves coursing the renalpelvis may be involved in sodium and fluid homeostasis. Inrats, capsaicin perfusion in one renal pelvis increased urineflow and urine sodium excretion in both kidneys. Thesechanges were abolished by capsazepine or preliminary ipsi-lateral kidney denervation (Zhu et al. 2005). If oral TRPV1antagonists become available, it may be interesting to see, ifbesides their effect in bladder inflammation, they also de-crease urine excretion, opening a promising application forthe treatment of nocturia.

TRPV1 immunoreactivity was also shown in transitionalcell tumours. Intense labelling was observed in low grade,low stage tumours, whereas very faint or absent labellingwas found in high grade, high stage ones (Lazzeri et al.2005). In addition, TRPV1 was described in the humancancer androgen-resistant cell line PC-3 (Sanchez et al.2005). Capsaicin was shown to induce apoptosis in this cellline by a mechanism involving oxidative stress, mitochon-drial changes and activation of caspase 3 (Sanchez et al.2006). However, apoptosis was not prevented by capsaze-pine, indicating that this effect was not mediated by TRPV1

(Sanchez et al. 2006). Nevertheless, if future studiesconfirm a role of TRPV1 in the differentiation of non-neuronal cells, a new promising field for TRPV1 investi-gation will be open.

Endogenous agonists of TRPV1 in the pathologicalbladder: the role of anandamide in cystitis

Endogenous TRPV1 agonists include protons (Tominaga etal. 1998), N-arachidonoyl-ethanolamine (anandamide)(Zygmunt et al. 1999), N-arachidonoyl-dopamine (Huanget al. 2002), N-oleoyl-dopamine, (Chu et al. 2003), lipo-oxygenase products, eicosanoid acids and leucotrienes(Hwang et al. 2000). Bradykinin does not bind TRPV1,but may activate the receptor indirectly through a bradyki-nin B2 receptor-mediated mechanism (Reeh and Petho2000). Other agents such as NGF, prostaglandins, oestro-gens, glutamate or ATP may contribute to TRPV1activation by inducing post-translational changes in thereceptor (Nagy et al. 2004, Szallasi 2006).

So far, in the bladder only anandamide has been tho-roughly studied as a TRPV1 endogenous agonist (Dinis et al.2004b). Mass spectrometric analysis revealed that cyclo-phosphamide-induced cystitis increased anandamide con-centration in the rat bladder in a persistent way (Fig. 7)Moreover, exogenous anandamide application or the block-ade of endogenous anandamide degradation in naivebladders increased pain-evoked gene expression in thespinal cord and the frequency of bladder reflex contractionsin a capsazepine dependent manner (Dinis et al. 2004b).

In addition to indicate that anandamide contributes forthe development of hyperalgesia and hyperreflexia duringcystitis through TRPV1 activation, two other interestingobservations were made. First, repeated anandamide appli-cations did not produce TRPV1 desensitisation (Dinis et al.2004b) strengthening the concept that anandamide and theexogenous agonists capsaicin and RTX act on differentbinding sites of the TRPV1 molecule (see Nagy et al. 2004for binding sites revision). Second, that the net effect ofanandamide, which is also a cannabinoid 1 (CB1) receptoragonist, resulted from the balance of actions mediated byTRPV1 and CB1 receptor. As a matter of fact, the blockadeof the CB1 receptor significantly increased the potency ofanandamide in enhancing bladder reflex activity (Dinis etal. 2004b). This suggests that anandamide has an excitatoryeffect on the bladder through TRPV1 and an inhibitory onethrough the CB1 receptor.

Recent studies have further implicated anandamide inTRPV1 activation under inflammatory conditions. In fact,the inflammatory mediators bradykinin and prostaglandinE2 were shown to increase the excitatory potency of anan-

Fig. 7 Average anandamide content of control and inflamed bladdersat different time points after intraperitoneal cyclophosphamideinjection. A significant increase is visible at all the time points.Reproduced from Dinis et al. 2004b


damide in nociceptive, capsaicin-sensitive, primary afferentneurons (Singh Tahim et al. 2005).

Clinical experience with TRPV1 agonists

Intravesical administration of vanilloids like capsaicin orresiniferatoxin was shown to be devoid of harmful effects tothe human bladder mucosa (Dasgupta et al. 1998; Silva et al.2001). This encouraged several groups of investigators toapply intravesically both compounds in order to desensitizecapsaicin sensitive sensory fibers. Two main indications forthis experimental treatment immediately emerged. One wasthe treatment of painful bladder syndromes including inter-stitial cystitis. The objective in this case was the inactiva-tion of bladder nociceptors, most of which are capsaicinsensitive (Habler et al. 1990; Sengupta and Gebhart 1994).The rationale for the other indication, the treatment of uri-nary incontinence due to bladder overactivity caused byspinal cord lesions, was elegantly given by De Groat(1997), based on the existence of two micturition reflexpathways fed by distinct bladder sensory input. Under in-tact spinal cord conditions micturition is controlled by avoluntary, supraspinal reflex pathway activated by sensoryinput conveyed in capsaicin resistant fibers. Spinal lesionsinterrupt this pathway and enhance a usually inactive reflexactivated by capsaicin sensitive input. The sacral reflextriggers involuntary bladder contractions during urine accu-mulation, leading to urinary incontinence (De Groat 1997).Desensitization induced by intravesical capsaicin or resin-iferatoxin would suppress that input.

Several open label studies and two small placebo-controlled trials conducted with capsaicin (Barbanti et al.1993; Cruz et al. 1997b; Lazzeri et al. 1996; Maggi et al.1989) or with RTX (Lazzeri et al. 1998, 2000, 2004)confirmed the clinical utility of intravesical capsaicin orRTX to reduce pain in patients with painful bladder syn-dromes including interstitial cystitis. The analgesic effectwas short-lived, approximately 4 weeks (Lazzeri et al.2000), unless repeated RTX applications were carried out(Lazzeri et al. 2004). Unexpectedly, the first large random-ized clinical trial in which several concentrations of RTXwere compared against placebo could not detect any ad-vantage in the use of the compound, whatever the con-centration chosen (Payne et al. 2005). Although noexplanation for the lack of effect was forwarded by theauthors, one can speculate how the 30 centers that par-ticipated in the study prepared the solutions. This informa-tion, although not given in the study, is decisive, since along interval between preparation and administrationgreatly reduces RTX activity. In addition, although treat-ment consisted of one single RTX instillation, patients werere-evaluated for the first time only at 4 weeks, a time pointat which previous studies (Lazzeri et al. 2000) had sug-gested that RTX started to loose efficacy. Obviously, thelack of effect of RTX might also indicate that other neuro-nal mechanisms besides TRPV1 are implicated in intersti-tial cystitis. These may include small-myelinated Aα fibersthat do not express the receptor (Roppolo et al. 2005) and/or purinergic mechanisms not involving directly TRPV1(Sun and Chai 2004, 2006).

Capsaicin was the first TRPV1 agonist used intravesicallyfor the treatment of bladder overactivity caused by spinalcord lesions (Cruz et al. 1997b; De Ridder et al. 1997; DeSéze et al. 1998; Fowler et al. 1992; Geirsson et al. 1995).In spite of increasing bladder capacity and decreasing oreven abolishing urinary incontinence in an important num-ber of patients, capsaicin was rapidly abandoned due to theintense neuronal excitation it induced (Raisinghani et al.2005) before desensitization took place. Such excitationwas perceived as an intense burning pain in the lower ab-domen, which could not be satisfactorily avoided even bypreliminary bladder anaesthesia (Cruz et al. 1997b). Incontrast, RTX causes a slow and sustained depolarizationwhile generating few action potentials (Raisinghani et al.2005), which can explain the low pungency reported bypatients during RTX application.

Most non-placebo controlled clinical trials with intra-vesical RTX included patients with incomplete spinal cordlesions (Brady et al. 2004a; Cruz et al. 1997a; De Séze et al.2004; Giannantoni et al. 2002, 2004; Kuo 2003a, Lazzeri etal. 1997; Silva et al. 2000). Methanalysis of these studiesindicates that RTX increases the bladder capacity by morethan 40% and decreases the number of incontinence epi-

Fig. 8 Mean volume to first involuntary detrusor contraction (FDC)and maximal cystometric capacity (MCC) are higher in the RTX thanin the placebo group at 3 months follow-up. Reproduced from Silva etal. 2005


sodes by 64%. These effects are long-lasting, up to9 months. A double blind, placebo controlled, randomizedclinical trial (Silva et al. 2005) confirmed RTX effects onbladder capacity (Fig. 8). In addition, it demonstrated thatthe discomfort reported by patients during RTX or placeboinstillation was similarly low (Silva et al. 2005). Interest-ingly, the density of TRPV1-IR fibers was shown to bestrongly increased in the bladder wall of patients withneurogenic bladder dysfunction, and was brought back tonormal by intravesical RTX (Brady et al. 2004a).

The enhancement of the sacral C-fiber driven micturitionreflex was also demonstrated in patients with benign prostaticenlargement (Chai et al. 1998; Yokoyama et al. 1994). It wassuggested that this reflex could trigger lower urinary tractsymptoms like urgency, frequency, nocturia and urge incon-tinence. Desensitization of C-fibers with intravesical RTX ina small group of such patients not only improved thesesymptoms but also increased bladder capacity without com-promising bladder emptying (Dinis et al. 2004c; Kuo2003b).

At the moment, RTX is available as a dry powder and notas a ready-to-use preparation. Stock ethanol solutions must,therefore, be prepared and kept at 4°C in glass containers. AsRTX is a lipophilic molecule (Szallasi and Blumberg 1992),working solutions should be prepared immediately beforetreatment. Bladder instillation of 50–100 nM solutions in10% ethanol can be carried out as an outpatient procedure,without preliminary local anaesthesia. However, the neces-sity of a local facility to prepare the solutions has limitedthe widespread therapeutic use of RTX.

Concluding remarks

The most surprising fact involving TRPV1 in the lowerurinary tract is the disproportion between its expression andthe little we know about its contribution to bladder function.Although initial studies have put emphasis in sensoryactivity, mainly pain perception and control of bladder reflexactivity in pathological states, it is exciting to see that theTRPV1 expression in cancer cells, urothelial and prostatic,may indicate that the receptor is involved in cellulardifferentiation.

The therapeutic benefit of exogenous TRPV1 agonists,such as capsaicin and RTX, that desensitize the receptor andinactivate the sensory fibers that express it, is at the momentvery restricted. Capsaicin is irritant when applied intravesi-cally. RTX, although exhibiting little irritancy, is not yetavailable in ready to administer pharmaceutical preparations.Nevertheless, taking in consideration the role of TRPV1 ininflammatory pain and bladder overactivity suggested byexperimental studies, RTX or specific TRPV1 antagonistsmay become relevant for the treatment of several lower

urinary tract dysfunctions. In addition, the recognition ofendogenous TRPV1 ligands may open new avenues thatshould be explored for therapeutic purposes. Clearly, in thisfield knowledge is still in its infancy.

Acknowledgements The authors would like to help Drs. AnaCharrua and Istvan Nagy for their scientific contributions and Dr.Célia Cruz for critical reading of the manuscript. This work wasfunded by FCT project POCTI/SAU-NEU/55983/2004.

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TRPV1 (vanilloid receptor) in the urinary tract: expression, function and clinical applications

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