Agents in early development for treatment of bladder dysfunction – promise of drugs acting at TRP channels?

ABSTRACT

Introduction: In the lower urinary tract (LUT) several members of the TRP superfamily are involved in nociception and mechanosensory transduction. Animal studies have suggested a therapeutic potential of some of these channels, including TRPV1, TRPV4, TRPM8, TRPA1, and TRPM4, for treatment of bladder over- and underactivity and bladder pain disorders, but translation of this information to clinical application has been slow.

Areas covered: An update on and discussion of current information on the potential clinical use of TRP channel agonists/antagonists in the treatment of different types of bladder dysfunction. The electronic databases PubMed and Scopus were used to identify relevant clinical and animal studies.

Expert opinion: The therapeutic effect of TRPV1 channel desensitizing agonists (capsaicin, resiniferatoxin, given intravesically) has been convincingly demonstrated in some forms of bladder overactivity. However, so far, the potential of any of the small-molecule TRP channel blockers developed for non-bladder indications and tested in early human trials for safety has not been explored clinically in LUT dysfunction. The adverse effects of hyperthermia and reduction of noxious heat sensation of the first generation TRPV1 blockers have delayed development. Despite lack of translational information, TRP channels remain interesting targets for future LUT drugs.

KEYWORDS:

• Lower urinary tract
• overactive bladder
• underactive bladder
• bladder pain
• TRPV1
• TRPV4
• TRPM8
• TRPA1
• TRPM4

1. introduction

For treatment of the overactive bladder (OAB) and detrusor overactivity (DO) antimuscarinic drugs, β₃‐adrenoceptor agonists, and botulinum toxin are currently the recommended pharmacological alternatives [1–4]. The pathophysiology of OAB is multifactorial [5,6], and new drug candidates are continuously being explored [3,7]. It has been suggested that among potential targets for future drugs aimed for OAB/DO treatment the different members of the TRP channel family may be one of the most promising [7]. Several of these channels are expressed in the bladder and may act as sensors of stretch and/or chemical irritation. OAB is a filling phase disorder and involves the generation of afferent impulses, implying that inhibition of these pathways can be effective for modulation of bladder afferent activity.

Even if the roles of these TRP channels in OAB/DO pathophysiology and treatment have not been established, there are reasons to believe that agonists/antagonists of some of these channels can be therapeutically useful not only in OAB/DO but also in other LUT disorders. The aim of this review is to give an update on and a critical discussion of current information on the potential clinical use of selected TRP channel agonists/antagonists in the treatment of different types of bladder dysfunction.

2. Search methodology

A search for literature relating to lower urinary tract (LUT) and TRP channels was performed. The electronic databases PubMed and Scopus were used to identify relevant clinical and animal studies. Keywords were entered as Medical Subject Headings (MeSH) or as text words. The Mesh terms were used in various combinations and usually included the terms bladder/urethra AND TRP channels. Other Mesh term used included; overactive bladder, detrusor overactivity, underactive bladder, detrusor underactivity, detrusor hyperactivity with impaired contractile function, interstitial cystitis, bladder pain syndrome. Clinical trials were searched at clinical trials.gov. Search results were assessed for their overall relevance to this review. There were no exclusion criteria.

3. LUT disorders as potential targets

OAB was defined in 2002 by the International Continence Society (ICS) as a storage symptom syndrome characterized by ‘urgency, with or without urgency urinary incontinence (UUI), usually with increased daytime frequency and nocturia’ [8]. The ICS also acknowledged within this definition that these symptoms are usually ‘suggestive of urodynamically demonstrable detrusor overactivity (DO) but can be due to other forms of urethra-vesical dysfunction’. DO is defined as ‘a urodynamic observation characterised by involuntary detrusor contractions during the filling phase which may be spontaneous or provoked’. DO has often been assumed to be synonymous with OAB; however, the presence of DO in only 50% of the female OAB patients has prompted further research on the mechanisms involved in the pathogenesis of OAB. Thus, the term OAB is often used both for the symptom complex (OAB syndrome) and for the urodynamic diagnosis (DO). The OAB syndrome, as originally defined, has unknown pathogenesis (idiopathic OAB) but may be e.g. neurogenic (NDO) as a consequence of injury to the brain or spinal cord.

Underactive bladder (UAB) has been described as a symptom syndrome reflecting the urodynamic observation of detrusor underactivity (DU), a voiding contraction of reduced strength and/or duration, leading to prolonged or incomplete bladder emptying [9]. UAB is characterized by a slow urinary stream, hesitancy and straining to void, with or without a feeling of incomplete bladder emptying and dribbling, often with storage symptoms.

A condition named detrusor hyperactivity with impaired contractile function (DHIC) was described by Resnick and Yalla [10]. Griffith et al. [11] suggested that DHIC “appeared to be a coincidental occurrence of two common conditions with different etiological factors. However, this was challenged by Chancellor [12] who suggested that “chronic untreated or treatment of refractory OAB – due to neurological diseases such as diabetes, bladder outlet obstruction or aging sarcopenia and frailty – may progress to DHIC and, finally, UAB. This would mean that effective treatment of OAB/DO would prevent the development of UAB/DU.

Pain during bladder filling can be associated with increased bladder activity. In bladder pain syndrome/interstitial cystitis (BPS/IC) frequency, urgency and nocturia together with pain, pressure, discomfort are common symptoms [13], and in these conditions drugs with effect on pain may decrease the bladder overactivity.

4. Rationale for use of drugs affecting TRP channels

In animal models of LUT disorders, an abundant number of reviews have reported promising effects of drugs acting on various types of TRP channels, including TRPV1, TRPV2, TRPV4, TRPM4, TRPM8 and TRPA1 (Figure 1;7,14–24). However, the amount of preclinical information about the roles of the different channels on LUT function/dysfunction varies widely and many of the animal models used have questionable translational value. It is obvious that a single animal model cannot mimick all aspects of the complexity of human disease. At best several models, each contributing to a piece of the puzzle is required to recreate a reasonable picture of the pathophysiology and time course of a disease and thus to identify reasonable targets for treatment. This makes it difficult to predict which agonist/antagonist that may be useful in what LUT disorder.

Figure 1. Main locations and functions of TRP channels in the bladder wall (see refs 16,24).

C-fiber afferents: TRPV1, TRPM8, TRPA1. The channels act as sensors of painful bladder stimuli or cold and as proalgesic and inflammatory mediators. They participate in the micturition reflex via afferent- and efferent-type signaling.A-delta fibers: TRPM8 mediates the bladder cooling reflex and is involved in the symptomatology and pathophysiology of idiopathic detrusor overactivity and painful bladder syndrome/interstitial cystitisUrothelium: TRPV4 is the principal urothelial mechanosensory. It is activated by bladder distention and modulates the micturition reflex via a urothelial signaling pathway. TRPV2 acts as a multimodal bladder sensor for detection of mechanical and neuroendocrine influences; it is also a determinant of urothelial carcinoma. The urothelial expression and function of TRPV1, TRPM8, TRPA1, and TRPM4 remain controversialDetrusor smooth muscle: TRPV4 is involved in the urothelium-independent contraction of isolated bladder strips. A similar expression pattern and function have been suggested for TRPV1, TRPV2, and TRPM4.Abbreviations: mm = muscularis mucosae; ic = interstitial cells

4.1. TRPV1

The pathophysiology of OAB has been subject to many speculations and many mechanisms relating to the roles of the urothelium, suburothelium, urethra, and central nervous system (CNS) in the pathogenesis have been discussed 5, 6). A common theme for OAB, DHIC, and BPS/IC is increased afferent signaling. Since TRP channels may be involved in mechanoreception and pain, they could, as mentioned above, be expected to be targeted for drugs aimed for treatment of these disorders.

The role of TRPV1 channels in normal human bladder function is still controversial. However, its role in the pathophysiology and treatment of particularly NDO has been well demonstrated [25,26]. NDO can be a consequence of spinal cord injury: the bladder is initially areflexic but then becomes hyperreflexic due to the emergence of a spinal micturition reflex pathway. The recovery of bladder function after spinal cord injury is dependent in part on the plasticity of bladder afferent pathways and the unmasking of reflexes triggered by unmyelinated, capsaicin-sensitive, C-fiber bladder afferent neurons [27]. The only agents, active at TRP channels, that have been used clinically for LUT disorders are the toxins capsaicin and resiniferatoxin (RTX), acting as TRPV1 agonists, and their application has been extensively reviewed elsewhere [28–32]. These toxins are considered to act by desensitizing the TRPV1 channel and inactivation of sensory neurons. In high concentrations, they may even irreversibly damage the neurons. However, there seems to be no further development of this principle for OAB or BPS/IC treatment.

It should be noted that there may be differences in complete inactivation of a sensory neuron by a toxin and blocking one of the receptors that convey afferent impulses by a small-molecule compound.

There is good preclinical evidence for the neuronal TRPV1 channel may have pathophysiological roles and contribute to bladder overactivity and pain in animal models [33], and that TRPV1 antagonists can be effective in these conditions. However, many TRPV1 antagonists are not without adverse effects, not surprising considering the wide distribution of TRPV1 receptors. The major adverse effects of the first generation of TRPV1 channel antagonists – a transient increase in body temperature and a reduction of noxious heat sensation leading to burn injuries – delayed the development. However, several TRPV1 blocking drugs without these adverse effects are now available [23].

A number of small-molecule TRPV1 antagonists are already undergoing Phase I/II clinical trials for the indications of chronic inflammatory pain and migraine [23]. However, information on agents for potential use in LUT disorders is lacking, even if several drugs have been tested in humans. In healthy subjects Round et al. [34] studied the safety and pharmacokinetics of the TRPV1 antagonist, XEN-D0501, being developed for treatment of OAB. They found a dose-related increase in body temperature which attenuated over time and was not considered to be of clinical concern. No data on bladder function were reported. XEN-D0501, which in preclinical capsaicin challenge studies showed superior efficacy and potency, was tested in 20 patients with refractory chronic cough in a double-blind, randomized, placebo-controlled crossover study [35]. No effects were found, ruling out TRPV1 as an effective therapeutic target for this disorder. NEO6860 is another TRPV1 antagonist, blocking capsaicin activation at the target [36]. The effects of the drug were tested in phase I, double-blind, placebo-controlled, ascending dose study on 64 healthy subjects. No clinically significant increase in temperature or heat pain threshold/tolerance was found and the drug was well tolerated. NEO6860 showed an improvement in the pharmacodynamics parameters investigated (evoked pain and secondary hyperalgesia). However, in a randomized, double-blinded, 3-period crossover, phase II study comparing NEO6860, placebo and naproxen in 54 patients with osteoarthritis knee pain, the drug did not statistically significantly outperform placebo. It did not affect body temperature and heat pain perception [37].

If any of these drugs will be tested in patients with LUT disorders is unclear, but the negative outcomes on other indications may have dampened the enthusiasm.

4.2. TRPV4

In mice and rats with cyclophosphamide-induced cystititis, HC-067047, a potent and selective TRPV4 antagonist increased functional bladder capacity and reduced micturition frequency [38]. DO induced by intravesical administration of a TRPV4 agonist in rats subjected to repeated variate stress (RVS) was improved by intravesical administration of HC067047, further suggesting that the TRPV4 channel could be a promising target for bladder function disorders [39].

Human experiences with TRPV4 antagonists are limited. GSK2798745 is a first-in-class, highly potent, selective, orally active TRPV4 channel blocker [40]. The drug was administered in a randomized, placebo-controlled study to healthy volunteers and to patients with stable heart failure. GSK279874 was found to be well tolerated and safe [41]. So far information concerning effects of HC067047 and GSK2798745 on human LUT does not seem to be available.

The effect profile of TRPV4 stimulation seems attractive for DU treatment. Deruyver et al. [42] administered the TRPV4 agonist, GSK1016790A, intravesically in a pelvic nerve injury rat model for DU. This model may reflect one type of neurogenic DU. They found that the drug increased voiding frequency and reduced postvoid residual in wild-type, but not TRPV4^−/- rats, and suggested TRPV4 stimulation as a possible treatment of DU. In support of this, Takaoka et al. [43], using a similar rat DU model, demonstrated that intravesical application of GSK1016790A significantly decreased intercontraction intervals, bladder capacity, voided volume, and post void residuals without increasing non-voiding contractions (NVCs), and that these effects were blocked by the TRPV4 antagonist RN1734. Again, if this can be translated to the clinical situation remains to be established.

4.3. TRPM8

Based on the positive correlation between the density of TRPM8 channels in the bladder mucosa and voiding frequency in IDO, and the increased TRPM8 expression in bladder pain patients, it was suggested that this channel was involved in the symptomatology and pathophysiology of these disorders [44]. Supporting this suggestion intravenous administration of the TRPM8 antagonist, AMTB, in the anesthetized rat decreased the frequency of volume-induced bladder contractions, without reducing the amplitude of contraction. AMTB significantly attenuated reflex responses to noxious urinary bladder distension [45], and it was suggested that targeting TRPM8 channel may provide a new therapeutic opportunity for DO/OAB and painful bladder syndromes.

The bladder cooling reflex (BCR) is a neonatal reflex that is positive in neurologically normal infants and young children. The BCR is suppressed at the time when the child gains full voluntary control of voiding. It may be unmasked by pathological processes and re-emerge in adults with IDO, as a consequence of loss of central descending inhibition due to conditions such as spinal cord injury or multiple sclerosis [46]. Even if the relationship between the bladder cooling reflex and the commonly experienced increase in urgency during exposure to low temperature is unclear, both may involve activation of TRPM8 receptors. Uvin et al. [47] applied innocuously cold stimuli to different parts of the skin and found that this induced rapid bladder contractions and voids in anesthetized mice and rats. The responses were strongly attenuated in Trpm8 ^−/-mice and in rats treated with AMTB supporting that it was mediated by inhibition of TRPM8 receptors. The authors suggested that TRPM8 channel blockers could be useful for treating acute cold-induced urgency symptoms in patients. If this suggestion is valid remains to be demonstrated.

TRPM8 channels have a widespread expression in the body and interference with their roles in various organ functions may be causing problems. Thus, even if published animal data suggest a therapeutic potential of TRPM8 antagonists to treat bladder hypersensitivity disorders, inhibition of the TRPM8 channel may lead to adverse effects that limit their clinical use. In preclinical models, inhibition of TRPM8 was shown to cause transient hypothermia. For example, Ito et al. [48] observed a dose-dependent decrease in deep body temperature after i.v. administration of the selective antagonist, RQ-00203078.

Information on effects of blocking TPM8 channels in man is scarce. PF-05105679, a selective TRPM8 antagonist, displayed a significant inhibition of pain in the cold pressor test and had no effect on core body temperature in humans. However, an unexpected adverse event (hot feeling) was reported, predominantly perioral which in two volunteers was non-tolerable [49]. This seems to have precluded further development.

4.4. TRPA1

TRPA1 channels functions as a sensor of noxious stimuli in the bladder of both animals and humans. The receptor is expressed in a subset of capsaicin-sensitive primary sensory neurons acting as a polymodal sensor for diverse physical and chemical stimuli of extracellular or intracellular origin. In the human urethra, TRPA1 channels have been demonstrated on urothelial cells and on C-fiber afferents in the lamina propria and detrusor muscle [50,51], and a role for TRPA1 in afferent and efferent sensory signaling of the human outflow region was suggested. Intravesical TRPA1 activators can initiate DO and a role in sensory transduction in the LUT has been supported by animal experiments [52–55].

Antagonists of TRPA1 receptors for pain treatment have been tested in humans, but none has reached the clinic [56].

4.5. TRPM4

The TRPM4 channel is a monovalent cation-selective channel activated by an increase of intracellular Ca²⁺. It is widely expressed in the body including rat, guinea pig, and human bladder urothelium and detrusor smooth muscle. The channel has been implicated in the regulation of many cellular processes, e.g. the immune response, insulin secretion, and bladder function [57].

Animal studies have suggested that TRPM4 could be a potential therapeutic target for detrusor overactivity. In isolated guinea-pig bladder smooth muscle strips, 9-phenanthrol, a selective inhibitor of the TRPM4 channel, reduced spontaneous contractions as well as contractions elicited by carbachol, KCl, and nerve stimulation [58–62]. Kullmann et al. [63], investigating the potential role of TRPM4 in detrusor overactivity following spinal cord transection (SCT) in mice, found that TRPM4 was upregulated in the urothelium and detrusor smooth muscle after the lesion. The spontaneous contractile activity of detrusor muscle strips in both spinally intact and STC mice was significantly reduced.

Even if the preclinical effects of TRPM4 activation and blockade could make the receptor an interesting target, there seem to be are no published experiences of e.g. TRPM4 blockade in humans.

5. Conclusion

The occurrence of several TRP channels in the lower urinary tract and the abundance of animal studies suggesting that blockade or stimulation of these channels can be therapeutically useful may give promise for the future. However, there are several reasons for dampening the enthusiasm for studies of LUT disorders, e.g. unreliability of animal models of LUT dysfunction and questionable efficacy of drugs tested in humans on other indications. It seems that despite new developments, ‘an enormous amount of work and dedication’ is needed before drug acting on TRP channels will become therapeutically useful for treatment of LUT disorders [64]. However, this does not exclude that TRP channels remain interesting targets for future LUT drugs.

6. Expert opinion

A great number of reviews have, based on promising effects in animal studies, predicted that agents interfering with TRP channels may have a future for treatment of different LUT disorders, e.g. OAB/DO, UAB/DU, and bladder pain. However, so far, the transition from animal experiment to clinical application has been slow, and presently available information on the use of TRP channel blockers in humans are restricted to Phase 1 studies on drugs intended to be used in LUT disorders (Table 1). So, so the question ‘are TRP inhibitors the next big thing in functional urology?’ [65] is presently difficult to answer. What is the current status?

Table 1. Preclinical and Clinical information of TRP channel agonist and antagonists.

TRP channel	Preclinical information	Clinical information
TRPV1	Agonists (capsaicin, resiniferatoxin)	Agonists (capsaicin, resiniferatoxin)
	Effective in bladder overactivity (e.g. neurogenic)	Effective in detrusor overactivity (e.g. NDO)
	and pain (e.g. refs 7,21,33)	and pain (Phase I–III; refs e.g. 28–33]
	Antagonists	Antagonists
	Effective in bladder overactivity and pain	Phase I–II (refs 23,34–37); no published information
	(refs e.g. 7,21,22,33)	on LUT disorders
TRPV4	Antagonists	Antagonists
	Effective in bladder overactivity	Phase I–II (ref 40); no published information on LUT disorders
	(refs e.g. 38,39)
	Agonists	Agonists
	Effective in DU (e.g. refs 42,43)	No published information
TRPM8	Antagonists	Antagonists
	Effective in bladder overactivity and pain	Phase I (ref 49); no published information on LUT disorders
	(refs e.g. 22,45,47,48)
TRPA1	Antagonists	Antagonists
	Effective in bladder overactivity and pain	Phase I–II (ref 56); no published information on LUT disorders
	(refs e.g. 22,52,55,56)
TRPM4	Antagonists	Antagonists
	Promising in vitro activity (refs 58–63)	No published information on LUT disorders

There is an abundance of new information from animal experiments suggesting that both agonists and antagonists of TRP channels may be useful for treatment of LUT disorders. This does not imply that effects demonstrated in different models of these disorders can be translated to clinical applications, since the translational impact of most models is low. Much of the enthusiasm for TRP channel activation/blockade as a treatment of LUT dysfunction has been based on the initial experiences with capsaicin and RTX. However, these toxins act by ‘desensitization’ or may be ‘defunctionalization’ of sensory neurons implying that the neuron is insensitive to all stimuli, temporarily or sometimes permanently [23]. This mechanism of action does not correspond to the consequences of blocking an individual TRP channel. Even if the actions of desensitizing toxins can be therapeutically effective there seem to be no new developments in the application of this principle in LUT disorders.

Most TRP channels are non-selective blockers of ion channels, are widely distributed in the body and appear to be involved in a number of physiological and pathophysiological mechanisms, implying that systemically administered agents will have an effect on other organ systems than the LUT. It is unclear if TRP channel agonists/antagonists with ‘uroselectivity’ [66] can be found. The existence of TRP channels unique for the lower urinary tract seems remote. However, this does not rule out that a specific TRP channel antagonist may have a “physiological/clinical uroselectivity implying that effect on LUT symptoms can be obtained without adverse effects from other organ systems. Systemic adverse effects may be avoided by if the TRP channel blockers were given intravesically. However, there seem to be no published studies on intravesical administration of these agents.

Two major adverse effects of, e.g. the first generation of TRPV1 channel antagonists tested for analgesic efficacy – a transient increase in body temperature and a long-lasting compromise of noxious heat sensation leading to burn injuries have tempered the enthusiasm for further development of such drugs for different indications, including LUT disorders. Several TRPV1 blocking drugs have been reported to have an improved balance between these adverse effects and those on pain, but the problems do not seem to have been solved [23].

New drugs for benign LUT disorders should be expected to have an efficacy/adverse effect relation at least comparable to existing alternatives. The currently approved/recommended drugs for OAB/DU have a reasonable efficacy/adverse effect relation. It may be questioned if there is any hope that TRP channel blockers should be either more effective or have a better adverse effects profile, or both, than existing pharmacological alternatives. Concerning the multifactorial pathophysiology of OAB [5] this does not seem very likely. The lack of efficacy in humans of several TRP channel blockers, showing promise in animal models of pain, is not encouraging, but does not exclude that some of them may have an effect on LUT disorders.

UAB also has a multifactorial pathophysiology and agents effective in this disorder are lacking. Theoretically, agents given intravesically for stimulation of bladder activity may be useful, and if the experiments with intravesical TRPV4 agonist reported in animal models [41,42] have any translational impact, this may have a therapeutic potential.

Presently it does not seem that TRP inhibitors are the next big thing in functional urology [65], but rather that the view expressed by Cruz in 2015: ‘TRP receptors are a reality that still needs an enormous amount of work and dedication before becoming therapeutically useful’ [64], is still valid.

Article Highlights

• TRP channels are widely distributed in the body and involved in many functions including nociception and mechanosensory transduction

• A therapeutic potential for drugs acting at TRP channels (e.g. TRPV1, TRPV4, TRPM8, TRPA1, and TRPM4) has been suggested for treatment of various lower urinary tract (LUT) disorders, including bladder over- and underactivity and bladder pain.

• An abundant amount of information is available on the effect of TRP channel agonists/antagonists in animal models of LUT disorders of bladder over- and underactivity and bladder pain, often with limited translational impact.

• Capsaicin and resiniferatoxin, acting as agonists at TRPV1 receptors, are the only TRP active agents with documented clinical effect on neurogenic bladder dysfunction. These toxins cause defunctionalization of sensory neurons.

• The potential of the small-molecule TRP channel blockers developed for non-bladder indications and tested in early human trials for safety has not been explored clinically in LUT dysfunction.

• The adverse effects of hyperthermia and reduction of noxious heat sensation of the first generation TRPV1 blockers have delayed development of new agents.

• Despite lack of translational information, TRP channels remain interesting targets for future LUT drugs.

This box summarizes key points contained in the article.

Declaration of interest

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