Transient receptor potential channel modulators as pharmacological treatments for lower urinary tract symptoms (LUTS): myth or reality?

Abstract

Transient receptor potential (TRP) channels belong to the most intensely pursued drug targets of the last decade. These ion channels are considered promising targets for the treatment of pain, hypersensitivity disorders and lower urinary tract symptoms (LUTS). The aim of the present review is to discuss to what extent TRP channels have adhered to their promise as new pharmacological targets in the lower urinary tract (LUT) and to outline the challenges that lie ahead.• TRP vanilloid 1 (TRPV1) agonists have proven their efficacy in the treatment of neurogenic detrusor overactivity (DO), albeit at the expense of prolonged adverse effects as pelvic 'burning' pain, sensory urgency and haematuria.• TRPV1 antagonists have been very successful in preclinical studies to treat pain and DO. However, clinical trials with the first generation TRPV1 antagonists were terminated early due to hyperthermia, a serious, on-target, side-effect.• TRP vanilloid 4 (TRPV4), TRP ankyrin 1 (TRPA1) and TRP melastatin 8 (TRPM8) have important sensory functions in the LUT. Antagonists of these channels have shown their potential in pre-clinical studies of LUT dysfunction and are awaiting clinical validation.

Receptors, channels, and signalling in the urothelial sensory system in the bladder

“…These receptors and ion channels include purinergic (such as P2X 1–7 and P2Y 1 , P2Y 2 , and P2Y 4 ) 2,27 (TABLE 1), adrenergic (α and β) 2 , cholinergic (muscarinic; M 1 –M 5 and nicotinic α 2 –α 10 , β 2 and β 4 ) 2 , protease-activated receptors 28 , acid sensing ion channels (ASIC) (such as ASIC2a and ASIC3) 29 , neurotrophin receptors (p75 NTR and tropomyosin receptor kinases A and B) 30–33 , CRF receptors 1 and 2 (REF. 21), transient receptor potential (TRP) (including TRPV1, TRPV2, TRPV4, TRPM7, TRPM8, TRPA1) channels 2,24,34–36 (TABLE 1), neuropeptide receptors (such as pituitary adenylyl cyclase-activating polypeptide (PACAP) type I receptor and vasoactive intestinal poly-peptide (VIP) receptor 2) 24,25,37 , and chemokine receptors (such as CXCR4, CX3CR1) 38 . The expression of these receptors and ion channels means that the urothelium can respond to diverse stimuli from many sources including: stretching and distension during bladder filling 2,24,34–36 , soluble factors such as nerve growth factor (NGF) 24 , neuroactive compounds such as PACAP 25 , VIP25 , CRF 21 , acetylcholine 2 , ATP or noradrenaline 2 (which are released from nerves and inflammatory cells), chemokines (including CXCL1, CXCL12, CX3CL1, CCL2), which are released from inflammatory cells 38–40 , and changes in pH resulting from inflammation 2,41 .…”

“…Multiple TRP channels from different subfamilies, including TRPV1, TRPV2, TRPV4, TRPM7, TRPM8, and TRPA1 are expressed in the urinary bladder, have specific tissue distributions in the LUT, are activated by numerous exogenous and endogenous mediators 34,35,50 (FIG. 3; TABLE 1), and might have functional roles in the micturition reflex 46,51 .…”

“…3; TABLE 1). The expression and function of TRPV1 channels in the bladder, specifically in the urothelium, is controversial 34,46 . Birder et al 18 described ATP release from cultured rat urothelial cells on application of the TRPV1 agonist, capsaicin, which was blocked by co-administration of the TRPV1 antagonist, capsazepine.…”

“…The intravesical administration of the TRPV1 activators, capsaicin or resiniferatoxin (TABLE 1), which desensitize afferent neurons, has been introduced into clinical practice for treatment of neurogenic detrusor overactivity (NDO) resulting in symptom improvement and major adverse effects 34,46,80 , emphasizing the need for the identification of additional targets (such as TRPV, TRPM, and TRPA channels and purinergic receptors and/or channels) (TABLE 1) that could result in improved urinary bladder function 81 . Intravesical instillation of capsaicin in patients with NDO reduced urinary frequency and urge incontinence and increased bladder capacity; however, treatment resulted in severe side effects (including bladder pain, suprapubic burning, bladder overactivity, and hot flashes) 34,46,80 making treatment poorly tolerated.…”

“…Intravesical instillation of capsaicin in patients with NDO reduced urinary frequency and urge incontinence and increased bladder capacity; however, treatment resulted in severe side effects (including bladder pain, suprapubic burning, bladder overactivity, and hot flashes) 34,46,80 making treatment poorly tolerated. Findings from two studies 82,83 have demonstrated that interaction between TRPV1 and anoctamin-1 (ANO1), a calcium-activated chloride channel, is a pain-enhancing mechanism in sensory neurons, suggesting that blockade of TRPV1–ANO1 interactions might be a novel analgesic target.…”