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Medicine, Research & Experimental
Capsaicin acts on sensory nerves via vanilloid receptors. TRPV1 has been extensively studied with respect to functional lower urinary tract (LUT) conditions in rodents and humans. Capsaicin (8-methyl-N-vanillyl-6-nonenamide) is a phenolic compound found in chili peppers that causes a burning sensation in mucous membranes. Other molecules that are structurally and functionally similar to capsaicin include capsaicinoids (dihydrocapsaicin, nordihydrocapsaicin, homodihydrocapsaicin and homocapsaicin), capsinoids (which are less potent) and the extremely potent resiniferoids, the best known of which is resiniferatoxin [1,2]. Capsaicin and resiniferatoxin have been extensively used to increase the understanding of functional lower urinary tract (LUT) disorders and to test in humans for the treatment of various LUT disorders.
- overactive bladder
- neurogenic detrusor overactivity
- interstitial cystitis
- pain bladder syndrome
1. Introduction
Capsaicin exerts a biphasic effect on the sensory nerves. Initial excitation is followed by a long-lasting blockade that renders C-fibers resistant to natural stimuli. It has been suggested that these effects result from its action on the vanilloid receptor [5]. The role of capsaicin-sensitive nerves in micturition was demonstrated by bladder instillation of capsaicin in individuals with bladder hypersensitivity disorders, which caused a concentration-related reduction in the first desire to void, bladder capacity and the pressure threshold for micturition, [6]. Those results led to the suggestion that intravesical capsaicin could desensitize sensory nerves and reduce bladder hypersensitivity (6], which was confirmed in a later study that demonstrated that a single intravesical capsaicin instillation reduced neurogenic detrusor overactivity for several months [7].
In 1997, the first vanilloid (capsaicin) receptor was cloned. It was named transient receptor potential vanilloid subfamily, member 1, TRPV1 [8]. This was the starting point for a large number of studies that showed the importance of this receptor for normal bladder function and its role in different types of bladder dysfunction. An in vivo model developed in healthy un-anesthetized rats showed that intravesical capsaicin induces reversible reliable concentration-dependent detrusor hyperactivity assessed by cystometry, which is abolished by intra-arterial hexamethonium administered near the bladder, or by intrathecal morphine [9]. The model was acute and easy to handle and the cystometry results were reliable. Since then, intravesical capsaicin has been widely used in rats to study OAB/DO, painful bladder syndrome/interstitial cystitis (PBS/IC), neurogenic detrusor overactivity (NDO) and bladder outlet obstruction (BOO)-related OAB/DO. It has been postulated that the dysfunction of bladder afferent signals is one of the mechanisms behind these conditions.
2. TRPV1 and Normal Bladder Function
Capsaicin exerts its actions by binding to the TRPV1 receptor/channel. The expression pattern and properties of the TRPV1 channels in the lower urinary tract have been well described [10,11,12]. TRPV1 is a non-selective cationic channel with high Ca2+ permeability that allows the passage of cations, mainly Ca2+. It is activated by vanilloids, noxious heat and low pH [8,13]. TRPV1 is the best-characterized member of the TRPV subfamily (TRPV1–6). Its morphology and function in animal models have been well described and several studies have determined the clinical effects of its manipulation [12,14,15]. However, the role of TRPV1 in normal human bladder function has not been fully determined. Cation influx through activated TRPV1 channels induces cell depolarization in afferent nerve fibers. This triggers an action potential, which in turn activates spinal reflexes and/or propagates to the brain to evoke conscious perception of bladder sensations. The depolarization also causes neuropeptide release, which could cause neurogenic inflammation by its action on the receptors of the released agents, e.g., substance P and CGRP.
Most bladder afferents are polymodal and respond to different chemical, thermal and mechanical stimuli, depending on the specific receptor subtypes that they express [16]. Approximately 75% of pelvic nerve fibers are mechanosensitive and respond to bladder stretch [17]. In urothelial cells, the influx of Ca2+ through different TRP channels initiates a myriad of Ca2+-dependent signaling responses.
A growing body of evidence suggests that, although the majority of afferent nerve fibers are located within the detrusor muscle, urothelial cells also contribute to mechano-sensation and chemo-sensation in the bladder. TRPV1 expression has been found in the suburothelial nerve plexus, detrusor smooth muscle and interstitial cells [12]. Thus, there is evidence of TRPV1 expression in small diameter bladder afferent fibers that lie close to the urothelium and also in bladder sensory neurons within the dorsal root ganglia (DRG).
The role of TRP channels in myogenic activation of afferents is unclear. Several TRP channels have been identified on detrusor muscle cells. TRPV1 channel agonists may have a direct contractile effect on detrusor muscle [18,19,20]. However, the roles of the urothelium and the interstitial cells (ICCs) in afferent activation are complex and have not yet been definitively established [21,22]. The secretion of adenosine triphosphate (ATP) by urothelial bladder cells is an important signal mediator, and suburothelial ICCs respond to purinergic stimulation by firing Ca2+ transients [23]. Suburothelial ICCs may be able to affect the activity of the detrusor myocytes [24,25,26].
3. Intravesical Capsaicin and Role of TRPV1 in LUT Dysfunction
3.1. Role of TPRV1 in Non-Neurogenic Overactive Bladder/Detrusor Overactivity
One study showed that TRPV1 expression was significantly higher in women with overactive bladder (OAB) than in women without OAB and that the increased expression was closely correlated to OAB occurrence [27]. Urodynamic variables including maximum flow rate (Qmax), first desire volume, strong desire to void volume, maximum cystometric capacity and bladder compliance were also lower in the individuals with OAB than those without. Likewise, Liu et al., [28] investigated patients with OAB symptoms who had no demonstrable detrusor overactivity (DO) but who had sensory urgency (early first sensation). Furthermore, TRPV1 expression levels in the trigone were inversely correlated with volume at first sensation during bladder filling. In contrast, TRPV1 expression levels were normal in individuals with idiopathic DO (IDO), suggesting sensory urgency and IDO distinct molecular bases [28]. Exposure at an early age to agents that affect TRPV1 channels may predispose to the later development of bladder dysfunction. This was demonstrated in a study in which the bladders of ten-day old rat pups were first desensitized with capsaicin, then sensitized with intravesical acetic acid diluted with saline [29]. Compared with a control group that did not undergo capsaicin desensitization, the acetic acid did not cause significant inflammation; however, it induced bladder sensitization that persisted into adulthood. This finding suggests that TRPV1 activation plays a role in inducing and maintaining bladder sensitization.
Social stress may be a cause of urinary bladder dysfunction in children that could continue into adulthood. Stress can trigger OAB by inducing TRPV1-dependent afferent nerve activity. This was demonstrated in six-week-old male C57BL/6 mice that were exposed to a C57BL/6 retired breeder aggressor mouse (in a barrier cage) [30]. Conscious cystometry was performed with and without intravesical infusion of the TRPV1 inhibitor, capsazepine evidenced that stress reduced in vivo inter-micturition interval and voided volume, which was restored by capsazepine intravesical infusion. Measured pressure–volume relationships and afferent nerve activity during bladder filling using an ex vivo bladder preparation suggested that, at low pressures, bladder compliance and afferent activity were elevated in the mice that were exposed to the stress compared with those that were not. A later study that used an intensified model of social stress demonstrated that TRPV1 channels are also implicated in the development of bladder decompensation and underactivity [31]; this finding suggests that treatments to prevent stress-induced bladder dysfunction in children should aim at TRPV1 receptors.
Evidence suggests that TRPV1-IR (immunoreactive) nerves are present throughout the whole urogenital tract, including the urethra, with capsaicin affecting both urethral smooth and striated muscles [32]. It has been speculated that DO may be initiated from the urethra [33] and, in females, a rapid pattern of urethral pressure variation (“unstable urethra”) seems to be closely associated with DO [34,35,36,37]. This raises the question of whether the TRPV1 channel is involved in urethral functions that can be linked to DO/OAB.
3.2. Role of TRPV1 in Neurogenic Detrusor Overactivity
Overactive bladder and voiding dysfunction are the most common symptoms of neurogenic lower urinary tract dysfunction [49,50]. The neurological dysfunction causes an inability to suppress spontaneous detrusor contractions. Neurogenic detrusor overactivity (NDO) may result from suprapontine or spinal cord lesions (above the lumbosacral level). Voluntary control of micturition is abolished by lesions situated above the lumbosacral cord level. This causes initial bladder areflexia and complete urinary retention but is followed by the slow development of a sacral spinal reflex mediated by formerly silent capsaicin-sensitive unmyelinated C-fibers. This reflex is triggered by low-volume bladder filling and causes NDO and detrusor external sphincter dyssynergia (DESD).
The emergence of bladder C-fiber reflexes may be mediated by neurotrophic factors, such as nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF). In rats, spinal cord injury (SCI) increases NGF production in the bladder, spinal cord and dorsal root ganglia. BDNF represses the growth of sensory afferents during the initial phase of spinal shock, thus protecting from bladder overactivity; however, once NDO has developed, BDNF appears to maintain the condition. Urothelium/suburothelium sensitization of afferent nerve fibers plays a role in the pathophysiology of NDO. Individuals with NDO have increased numbers of suburothelial nerve fibers that are immunoreactive to P2X3 compared with healthy controls.
Evidence suggests that NDO is mediated by capsaicin-sensitive C-fiber afferents, and the role of TRPV1 in the pathophysiology and treatment of neurogenic detrusor overactivity (NDO) has been well demonstrated [51,52,53]. Studies of individuals with NDO found increased immunoreactivity of PGP9.5 (nerve stain) and TRPV1 in the suburothelium and basal layers of the urothelium compared with controls. TRPV1 immunoreactivity was significantly lower in individuals with NDO who responded clinically to intravesical resiniferatoxin (RTX), which suggests that TRPV1 is involved in the pathophysiology of NDO [51,52,53]. However, the effects of vanilloids (capsaicin, RTX) on urothelial TRPV1 indicates that vanilloid actions are more complex than simple C-fiber desensitization.
In people with NDO, the sacral micturition reflex is inactivated by C-fiber desensitization [54]. This sacral reflex emerges after chronic spinal cord lesions above the sacral level of the sacral level [54,55,56]. Neuronal and urothelial TRPV1 expression is increased in the bladder in people with NDO [51,57], and the degree of expression is correlated with urgency sensation [28]. Intravesical application of vanilloids lowers TRPV1 expression [52,53].
3.3. Role of TRPV1 in Painful Bladder Syndrome/Interstitial Cystitis (PBS/IC)
Painful bladder syndrome/interstitial cystitis (PBS/IC) causes persistent pelvic pain and lower urinary tract symptoms that reduce the quality of life of affected individuals. The phenotypes and etiologies of this condition vary widely.
No predictive animal models of PBS/IC currently exist [69]. Cyclophosphamide-induced bladder overactivity has been widely used but does not reflect all the characteristics of the disorder. Evidence from pathological and genomic studies suggests that PBS/IC should be categorized according to whether Hunner lesions are present (IC) or not (PBS) and not by clinical phenotyping according to the symptoms experienced [70]. IC may constitute a separate entity. Studies have found TRPV1 immunoreactivity to be altered in individuals with PBS/IC, which suggests that TRPV1 channels are involved in the pathogenesis of PBS/IC. Bladder biopsies from individuals with PBS who met the National Institute for Diabetes and Digestive and Kidney Diseases (NIDDK) research criteria for IC showed increased TRPV1 immunoreactivity within the nerve fibers compared with biopsies from individuals with asymptomatic microscopic hematuria [71]. Furthermore, pain ratings were correlated with the relative density of TRPV1 nerve fibers. Another study also involving bladder biopsies from individuals with IC/BPS who met the NIDDK research criteria found increased severity of inflammation that was correlated with a higher TRPV1 immunoreactive nerve fiber density and higher NGF levels [72] compared with control participants. Suburothelial TRPV1-immunoreactive nerve fiber density was significantly correlated with pain scores and urgency scores. The density of PGP9.5-immunoreactive nerve fibers was significantly increased in those with IC/BPS and was positively correlated with inflammation severity. Thus, higher levels of expression of TRPV1-immunoreactive nerve fibers and NGF cause more severe inflammation and clinical symptoms in IC/BPS.
3.4. Role of TRPV1 in Bladder Disorders Caused by Bladder Outlet Obstruction
Comparison of the involvement of tachykinins via NK1 receptors in the micturition reflex induced by bladder filling in normal rats and in rats with bladder hypertrophy due to BOO has shown that the increase in the afferent input from the bladder to the dorsal root ganglion during bladder filling is at least partly conveyed by capsaicin-sensitive afferents and even more so in the BOO rat [83]. The ice water test (IWT) was developed for clinical practice to identify C-fiber involvement in the micturition reflex by detecting uninhibited detrusor contractions after instillation of iced water into the bladder. The response rate is considerably higher in individuals with neurological disease than those without (around 70% versus 27%). However, among responders with no known neurological disease, the degree of BOO was found to be significantly greater than in non-responders [84]. Positive responses to the IWT have also been reported in individuals with BPH/BOO [85]: 71% of individuals with BOO responded compared with 7% in those with no BOO.
4. Clinical Application of Drugs Blocking TRPV1 Receptors
Despite capsaicin and resiniferatoxin blocking TRPV1 receptors by causing receptor desensitization seeming to have efficacy in the treatment of neurogenic bladder, they are currently rarely or no longer used clinically [89]. As mentioned previously, based on results from several animal models of LUT disorders, selective TRPV1 antagonists appear to be promising drug candidates. However, polymodal first generation selective TRPV1 antagonists cause hyperthermia, both in animal models and in humans [90,91], which limits their clinical application. Second-generation (mode-selective) TRPV1 antagonists potently block channel activation by capsaicin, but exert different effects (e.g., potentiation, no effect, or low-potency inhibition) in the proton mode, heat mode or both [91]. Brown et al., [92] conducted a phase I study in healthy volunteers on the safety and pharmacokinetics of oral NEO6860, a modality selective TRPV1 antagonist, and found no clinically significant increase in temperature or heat pain threshold/tolerance, but a significant antagonistic effect on intra-dermal capsaicin-induced pain. A large number of TRPV1 antagonists has been tested in phase I studies [91], but few have been further developed [93] and none has so far been approved [91,92,93]. There seems to be no published proof-of-concept studies on LUT disorders.
This entry is adapted from the peer-reviewed paper 10.3390/medsci10030050
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