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

Figures & data

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

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

Skryma R, Prevarskaya N, Gkika D, et al. From urgency to frequency: facts and controversies of TRPs in the lower urinary tract. Nat Rev Urol. 2011 Oct 4;8(11):617–630.

 PubMed Web of Science ®Google Scholar

Andersson KE. TRP channels as lower urinary tract sensory targets. Med Sci (Basel). 2019 May 22;7(5):pii: E67.

 PubMedGoogle Scholar

Andersson KE. Potential future pharmacological treatment of bladder dysfunction. Basic Clin Pharmacol Toxicol. 2016 Oct;119(Suppl 3):75–85. .

 PubMedGoogle Scholar

Merrill L, Gonzalez EJ, Girard BM, et al. Receptors, channels, and signalling in the urothelial sensory system in the bladder. Nat Rev Urol. 2016 Apr;13(4):193–204.

 PubMed Web of Science ®Google Scholar

Avelino A, Cruz F. TRPV1 (vanilloid receptor) in the urinary tract: expression, function and clinical applications. Naunyn Schmiedebergs Arch Pharmacol. 2006 Jul;373(4):287–299.

 PubMed Web of Science ®Google Scholar

Cruz F, Dinis P. Resiniferatoxin and botulinum toxin type A for treatment of lower urinary tract symptoms. Neurourol Urodyn. 2007 Oct;26(6 Suppl):920–927.

 PubMed Web of Science ®Google Scholar

Moran MM, Szallasi A. Targeting nociceptive transient receptor potential channels to treat chronic pain: current state of the field. Br J Pharmacol. 2018 Jun;175(12):2185–2203.

 PubMed Web of Science ®Google Scholar

Round P, Priestley A, Robinson J. An investigation of the safety and pharmacokinetics of the novel TRPV1 antagonist XEN-D0501 in healthy subjects. Br J Clin Pharmacol. 2011 Dec;72(6):921–931.

 PubMed Web of Science ®Google Scholar

Arsenault P, Chiche D, Brown W, et al. NEO6860, modality-selective TRPV1 antagonist: a randomized, controlled, proof-of-concept trial in patients with osteoarthritis knee pain. Pain Rep. 2018 Oct 26;3(6):e696. eCollection 2018 Nov.

 PubMedGoogle Scholar

Moran MM. TRP channels as potential drug targets. Annu Rev Pharmacol Toxicol. 2018Jan6;58:309–330.

 PubMed Web of Science ®Google Scholar

Cheung M, Bao W, Behm DJ, et al. Discovery of GSK2193874: an orally active, potent, and selective blocker of transient receptor potential vanilloid 4. ACS Med Chem Lett. 2017 Mar 20;8(5):549–554. eCollection 2017 May 11.

 PubMed Web of Science ®Google Scholar

Everaerts W, Zhen X, Ghosh D, et al. Inhibition of the cation channel TRPV4 improves bladder function in mice and rats with cyclophosphamide-induced cystitis. Proc Natl Acad Sci U S A. 2010 Nov 2;107(44):19084–19089.

 PubMed Web of Science ®Google Scholar

Merrill L, Vizzard MA. Intravesical TRPV4 blockade reduces repeated variate stress-induced bladder dysfunction by increasing bladder capacity and decreasing voiding frequency in male rats. Am J Physiol Regul Integr Comp Physiol. 2014 Aug 15;307(4):R471–80.

 PubMed Web of Science ®Google Scholar

Deruyver Y, Weyne E, Dewulf K, et al. Intravesical activation of the cation channel TRPV4 improves bladder function in a rat model for detrusor underactivity. Eur Urol. 2018 Sep;74(3):336–345.

 PubMed Web of Science ®Google Scholar

Takaoka EI, Kurobe M, Okada H, et al. Effect of TRPV4 activation in a rat model of detrusor underactivity induced by bilateral pelvic nerve crush injury. Neurourol Urodyn. 2018 Nov;37(8):2527–2534.

 PubMed Web of Science ®Google Scholar

Winchester WJ, Gore K, Glatt S, et al. Inhibition of TRPM8 channels reduces pain in the cold pressor test in humans. J Pharmacol Exp Ther. 2014 Nov;351(2):259–269.

 PubMed Web of Science ®Google Scholar

Lashinger ES, Steiginga MS, Hieble JP, et al. AMTB, a TRPM8 channel blocker: evidence in rats for activity in overactive bladder and painful bladder syndrome. Am J Physiol Renal Physiol. 2008 Sep;295(3):F803–10.

 PubMed Web of Science ®Google Scholar

Uvin P, Franken J, Pinto S, et al. Essential role of transient receptor potential M8 (TRPM8) in a model of acute cold-induced urinary urgency. Eur Urol. 2015 Oct;68(4):655–661.

 PubMed Web of Science ®Google Scholar

Ito H, Aizawa N, Sugiyama R, et al. Functional role of the transient receptor potential melastatin 8 (TRPM8) ion channel in the urinary bladder assessed by conscious cystometry and ex vivo measurements of single-unit mechanosensitive bladder afferent activities in the rat. BJU Int. 2016 Mar;117(3):484–494.

 PubMed Web of Science ®Google Scholar

Koivisto A, Jalava N, Bratty R, et al. TRPA1 antagonists for pain relief. Pharmaceuticals (Basel). 2018 Nov 1;11(4):pii: E117.

 PubMedGoogle Scholar

Du S, Araki I, Kobayashi H, et al. Differential expression profile of cold (TRPA1) and cool (TRPM8) receptors in human urogenital organs. Urology. 2008 Aug;72(2):450–455.

 PubMed Web of Science ®Google Scholar

Nicholas S, Yuan SY, Brookes SJ, et al. Hydrogen peroxide preferentially activates capsaicin-sensitive high threshold afferents via TRPA1 channels in the guinea pig bladder. Br J Pharmacol. 2017 Jan;174(2):126–138.

 PubMed Web of Science ®Google Scholar

Smith AC, Hristov KL, Cheng Q, et al. Novel role for the transient potential receptor melastatin 4 channel in guinea pig detrusor smooth muscle physiology. Am J Physiol Cell Physiol. 2013 Mar 1;304(5):C467–77.

 PubMed Web of Science ®Google Scholar

Kullmann FA, Beckel JM, McDonnell B, et al. Involvement of TRPM4 in detrusor overactivity following spinal cord transection in mice. Naunyn Schmiedebergs Arch Pharmacol. 2018 Nov;391(11):1191–1202.

 PubMed Web of Science ®Google Scholar