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

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

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper is not funded.