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

BJU International

Volumn 115, Issue 5, 2015, Pages 686-697

  Deruyver, Yves ^a,c,d   Voets, Thomas ^b,d   De Ridder, Dirk ^a,c,d   Everaerts, Wouter ^a,d,e  

^a SKELETAL BIOLOGY AND ENGINEERING RESEARCH CENTER   (Belgium)

^b UNIVERSITY OF LEUVEN   (Belgium)

^c UNIVERSITY HOSPITALS LEUVEN   (Belgium)

^d TRP Research Platform Leuven   (Belgium)

^e ROYAL MELBOURNE HOSPITAL   (Australia)

Author keywords

afferent nerve; detrusor overactivity; LUTS; TRP channel; TRPV1; TRPV4; urothelium

Indexed keywords

4 [3 (TRIFLUOROMETHYL) 2 PYRIDINYL] N [5 (TRIFLUOROMETHYL) 2 PYRIDINYL] 1 PIPERAZINECARBOXAMIDE; ALGRX 4957; BOTULINUM TOXIN; CAPSAICIN; CYCLOPHOSPHAMIDE; D 3263; GRC 17536; GSK 1016790A; GSK 2193874; GSK 2798745; HC 067047; JTS 653; LIPOPOLYSACCHARIDE; N (4 ISOPROPYLPHENYL) 2 (1,2,3,6 TETRAHYDRO 1,3 DIMETHYL 2,6 DIOXO 7H PURIN 7 YL)ACETAMIDE; N (4 TERT BUTYLPHENYL) 4 (3 CHLORO 2 PYRIDINYL) 1 PIPERAZINECARBOXAMIDE; N [4 [6 [4 (TRIFLUOROMETHYL)PHENYL] 4 PYRIMIDINYLOXY]BENZOTHIAZOL 2 YL]ACETAMIDE; NEUROPEPTIDE; PLACEBO; PROSTAGLANDIN; RESINIFERATOXIN; TRANSIENT RECEPTOR POTENTIAL CHANNEL M8; UNCLASSIFIED DRUG; VANILLOID RECEPTOR 1; VANILLOID RECEPTOR 1 ANTAGONIST; VANILLOID RECEPTOR 4; VANILLOID RECEPTOR 4 ANTAGONIST; VANILLOID RECEPTOR ANTAGONIST; XEND 0501; ZUCACAPSAICIN; TRANSIENT RECEPTOR POTENTIAL CHANNEL;

ANTIBODY SPECIFICITY; APOPTOSIS; BLADDER CONTRACTION; BLADDER DISTENSION; BLADDER DYSFUNCTION; BONE DYSPLASIA; BRACHYOLMIA TYPE 3; CELL DIFFERENTIATION; COLD STRESS; CONGENITAL DISTAL SPINAL MOTOR NEUROPATHY; CYSTITIS; DRUG EFFICACY; DRUG SAFETY; DRUG TOLERABILITY; DRUG TOLERANCE; ENZYME ACTIVATION; ENZYME ACTIVITY; ENZYME RELEASE; HEART FAILURE; HEMATURIA; HEREDITARY MOTOR SENSORY NEUROPATHY; HOT FLUSH; HUMAN; HYPERREFLEXIA; HYPERSENSITIVITY; HYPERTENSION; HYPERTHERMIA; HYPOTHERMIA; IDIOPATHIC DETRUSOR OVERACTIVITY; IMMUNOREACTIVITY; IN VITRO STUDY; IN VIVO STUDY; INCIDENCE; INFLAMMATION; INTERSTITIAL CYSTITIS; LOWER URINARY TRACT SYMPTOM; MOTOR NEUROPATHY; NEUROGENIC DETRUSOR OVERACTIVITY; NONHUMAN; OVERACTIVE BLADDER; PAIN; PELVIC PAIN; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PILOT STUDY; POLLAKISURIA; POSTHERPETIC NEURALGIA; PRIORITY JOURNAL; PROSTATE CANCER; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN SECRETION; RANDOMIZED CONTROLLED TRIAL (TOPIC); RECEPTOR DOWN REGULATION; REVIEW; SENSORY DYSFUNCTION; SENSORY URGENCY; SINGLE DRUG DOSE; SOLID TUMOR; SPINAL CORD INJURY; SYNAPTIC TRANSMISSION; URGE INCONTINENCE; URINARY FREQUENCY; URINARY URGENCY; UROTHELIUM; AGONISTS; ANTAGONISTS AND INHIBITORS; LOWER URINARY TRACT SYMPTOMS;

HUMANS; LOWER URINARY TRACT SYMPTOMS; TRANSIENT RECEPTOR POTENTIAL CHANNELS;

EID: 84927913406     PISSN: 14644096     EISSN: 1464410X     Source Type: Journal    
DOI: 10.1111/bju.12876     Document Type: Review

References (99)

1. Nilius B,. TRP channels in disease. Biochim Biophys Acta 2007; 1772: 805-812
2. Kanai A, Andersson KE,. Bladder afferent signaling: recent findings. J Urol 2010; 183: 1288-1295
3. Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D,. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 1997; 389: 816-824
4. Geppetti P, Nassini R, Materazzi S, Benemei S,. The concept of neurogenic inflammation. BJU Int 2008; 101 (Suppl. 3): 2-6
5. Avelino A, Cruz C, Nagy I, Cruz F,. Vanilloid receptor 1 expression in the rat urinary tract. Neuroscience 2002; 109: 787-798
6. Yu W, Hill WG, Apodaca G, Zeidel ML,. Expression and distribution of transient receptor potential (TRP) channels in bladder epithelium. Am J Physiol Renal Physiol 2011; 300: F49-59
7. Yiangou Y, Facer P, Ford A, et-al. Capsaicin receptor VR1 and ATP-gated ion channel P2X3 in human urinary bladder. BJU Int 2001; 87: 774-779
8. Birder LA, Kanai AJ, de Groat WC, et-al. Vanilloid receptor expression suggests a sensory role for urinary bladder epithelial cells. Proc Natl Acad Sci USA 2001; 98: 13396-13401
9. Kullmann FA, Shah MA, Birder LA, de Groat WC,. Functional TRP and ASIC-like channels in cultured urothelial cells from the rat. Am J Physiol Renal Physiol 2009; 296: F892-901
10. Charrua A, Reguenga C, Cordeiro JM, et-al. Functional transient receptor potential vanilloid 1 is expressed in human urothelial cells. J Urol 2009; 182: 2944-2950
11. Xu X, Gordon E, Lin Z, Lozinskaya IM, Chen Y, Thorneloe KS,. Functional TRPV4 channels and an absence of capsaicin-evoked currents in freshly-isolated, guinea-pig urothelial cells. Channels (Austin) 2009; 3: 156-160
12. Everaerts W, Vriens J, Owsianik G, et-al. Functional characterization of transient receptor potential channels in mouse urothelial cells. Am J Physiol Renal Physiol 2010; 298: F692-701
13. Yamada T, Ugawa S, Ueda T, Ishida Y, Kajita K, Shimada S,. Differential localizations of the transient receptor potential channels TRPV4 and TRPV1 in the mouse urinary bladder. J Histochem Cytochem 2009; 57: 277-287
14. Mochizuki T, Sokabe T, Araki I, et-al. The TRPV4 cation channel mediates stretch-evoked Ca2+ influx and ATP release in primary urothelial cell cultures. J Biol Chem 2009; 284: 21257-21264
15. O'Mullane LM, Keast JR, Osborne PB,. Co-cultures provide a new tool to probe communication between adult sensory neurons and urothelium. J Urol 2013; 190: 737-745
16. Shabir S, Cross W, Kirkwood LA, et-al. Functional expression of purinergic P2 receptors and transient receptor potential channels by the human urothelium. Am J Physiol Renal Physiol 2013; 305: F396-406
17. Cavanaugh DJ, Chesler AT, Jackson AC, et-al. Trpv1 reporter mice reveal highly restricted brain distribution and functional expression in arteriolar smooth muscle cells. J Neurosci 2011; 31: 5067-5077
18. Everaerts W, Sepulveda MR, Gevaert T, Roskams T, Nilius B, De Ridder D,. Where is TRPV1 expressed in the bladder, do we see the real channel? Naunyn Schmiedebergs Arch Pharmacol 2009; 379: 421-425
19. Birder LA, Nakamura Y, Kiss S, et-al. Altered urinary bladder function in mice lacking the vanilloid receptor TRPV1. Nat Neurosci 2002; 5: 856-860
20. Daly D, Rong W, Chess-Williams R, Chapple C, Grundy D,. Bladder afferent sensitivity in wild-type and TRPV1 knockout mice. J Physiol 2007; 583: 663-674
21. Dinis P, Charrua A, Avelino A, et-al. Anandamide-evoked activation of vanilloid receptor 1 contributes to the development of bladder hyperreflexia and nociceptive transmission to spinal dorsal horn neurons in cystitis. J Neurosci 2004; 24: 11253-11263
22. Saitoh C, Kitada C, Uchida W, Chancellor MB, de Groat WC, Yoshimura N,. The differential contractile responses to capsaicin and anandamide in muscle strips isolated from the rat urinary bladder. Eur J Pharmacol 2007; 570: 182-187
23. Wang ZY, Wang P, Merriam FV, Bjorling DE,. Lack of TRPV1 inhibits cystitis-induced increased mechanical sensitivity in mice. Pain 2008; 139: 158-167
24. Charrua A, Cruz CD, Cruz F, Avelino A,. Transient receptor potential vanilloid subfamily 1 is essential for the generation of noxious bladder input and bladder overactivity in cystitis. J Urol 2007; 177: 1537-1541
25. Brady CM, Apostolidis AN, Harper M, et-al. Parallel changes in bladder suburothelial vanilloid receptor TRPV1 and pan-neuronal marker PGP9.5 immunoreactivity in patients with neurogenic detrusor overactivity after intravesical resiniferatoxin treatment. BJU Int 2004; 93: 770-776
26. Maggi CA, Lecci A, Santicioli P, Del Bianco E, Giuliani S,. Cyclophosphamide cystitis in rats: involvement of capsaicin-sensitive primary afferents. J Auton Nerv Syst 1992; 38: 201-208
27. Everaerts W, Gevaert T, Nilius B, De Ridder D,. On the origin of bladder sensing: Tr(i)ps in urology. Neurourol Urodyn 2008; 27: 264-273
28. de Groat WC, Kawatani M, Hisamitsu T, et-al. Mechanisms underlying the recovery of urinary bladder function following spinal cord injury. J Auton Nerv Syst 1990; 30 (Suppl.): S71-77
29. Wong GY, Gavva NR,. Therapeutic potential of vanilloid receptor TRPV1 agonists and antagonists as analgesics: recent advances and setbacks. Brain Res Rev 2009; 60: 267-277
30. Maggi CA, Barbanti G, Santicioli P, et-al. Cystometric evidence that capsaicin-sensitive nerves modulate the afferent branch of micturition reflex in humans. J Urol 1989; 142: 150-154
31. de Seze M, Wiart L, Joseph PA, Dosque JP, Mazaux JM, Barat M,. Capsaicin and neurogenic detrusor hyperreflexia: a double-blind placebo-controlled study in 20 patients with spinal cord lesions. Neurourol Urodyn 1998; 17: 513-523
32. Wiart L, Joseph PA, Petit H, et-al. The effects of capsaicin on the neurogenic hyperreflexic detrusor. A double blind placebo controlled study in patients with spinal cord disease. Preliminary results. Spinal Cord 1998; 36: 95-99
33. de Seze M, Gallien P, Denys P, et-al. Intravesical glucidic capsaicin versus glucidic solvent in neurogenic detrusor overactivity: a double blind controlled randomized study. Neurourol Urodyn 2006; 25: 752-757
34. Petersen T, Nielsen JB, Schroder HD,. Intravesical capsaicin in patients with detrusor hyper-reflexia-a placebo-controlled cross-over study. Scand J Urol Nephrol 1999; 33: 104-110
35. Kim JH, Rivas DA, Shenot PJ, et-al. Intravesical resiniferatoxin for refractory detrusor hyperreflexia: a multicenter, blinded, randomized, placebo-controlled trial. J Spinal Cord Med 2003; 26: 358-363
36. Silva C, Silva J, Ribeiro MJ, Avelino A, Cruz F,. Urodynamic effect of intravesical resiniferatoxin in patients with neurogenic detrusor overactivity of spinal origin: results of a double-blind randomized placebo-controlled trial. Eur Urol 2005; 48: 650-655
37. de Seze M, Wiart L, de Seze MP, et-al. Intravesical capsaicin versus resiniferatoxin for the treatment of detrusor hyperreflexia in spinal cord injured patients: a double-blind, randomized, controlled study. J Urol 2004; 171: 251-255
38. Giannantoni A, Di Stasi SM, Stephen RL, et-al. Intravesical capsaicin versus resiniferatoxin in patients with detrusor hyperreflexia: a prospective randomized study. J Urol 2002; 167: 1710-1714
39. Lim EK, Kuo HC,. The treatment of overactive bladder syndrome refractory to antimuscarinic therapy. Incont Pelvic Floor Dysfunc 2008; 2 (Suppl. 1): 29-32
40. Di Stasi S, Giannantoni A, Massoud R, et-al. Stability of resiniferatoxin stock solutions. Eur Urol Suppl 2004; 3: 106
41. de Seze M, Wiart L, Ferriere J, de Seze MP, Joseph P, Barat M,. Intravesical instillation of capsaicin in urology: a review of the literature. Eur Urol 1999; 36: 267-277
42. MacDonald R, Monga M, Fink HA, Wilt TJ,. Neurotoxin treatments for urinary incontinence in subjects with spinal cord injury or multiple sclerosis: a systematic review of effectiveness and adverse effects. J Spinal Cord Med 2008; 31: 157-165
43. Lazzeri M, Beneforti P, Benaim G, Maggi CA, Lecci A, Turini D,. Intravesical capsaicin for treatment of severe bladder pain: a randomized placebo controlled study. J Urol 1996; 156: 947-952
44. Payne CK, Mosbaugh PG, Forrest JB, et-al. Intravesical resiniferatoxin for the treatment of interstitial cystitis: a randomized, double-blind, placebo controlled trial. J Urol 2005; 173: 1590-1594
45. Ham BK, Kim JH, Oh MM, Lee JG, Bae JH,. Effects of combination treatment of intravesical resiniferatoxin instillation and hydrodistention in patients with refractory painful bladder syndrome/interstitial cystitis: a pilot study. Int Neurourol J 2012; 16: 41-46
46. Kuo HC, Liu HT, Yang WC,. Therapeutic effect of multiple resiniferatoxin intravesical instillations in patients with refractory detrusor overactivity: a randomized, double-blind, placebo controlled study. J Urol 2006; 176: 641-645
47. Rios LA, Panhoca R, Mattos D Jr, Srugi M, Bruschini H,. Intravesical resiniferatoxin for the treatment of women with idiopathic detrusor overactivity and urgency incontinence: a single dose, 4 weeks, double-blind, randomized, placebo controlled trial. Neurourol Urodyn 2007; 26: 773-778
48. Silva C, Silva J, Castro H, et-al. Bladder sensory desensitization decreases urinary urgency. BMC Urol 2007; 7: 9
49. Charrua A, Cruz CD, Narayanan S, et-al. GRC-6211, a new oral specific TRPV1 antagonist, decreases bladder overactivity and noxious bladder input in cystitis animal models. J Urol 2009; 181: 379-386
50. Santos-Silva A, Charrua A, Cruz CD, Gharat L, Avelino A, Cruz F,. Rat detrusor overactivity induced by chronic spinalization can be abolished by a transient receptor potential vanilloid 1 (TRPV1) antagonist. Auton Neurosci 2012; 166: 35-38
51. Kitagawa Y, Wada M, Kanehisa T, et-al. JTS-653 blocks afferent nerve firing and attenuates bladder overactivity without affecting normal voiding function. J Urol 2013; 189: 1137-1146
52. Cefalu JS, Guillon MA, Burbach LR, et-al. Selective pharmacological blockade of the TRPV1 receptor suppresses sensory reflexes of the rodent bladder. J Urol 2009; 182: 776-785
53. Moran MM, McAlexander MA, Biro T, Szallasi A,. Transient receptor potential channels as therapeutic targets. Nat Rev Drug Discov 2011; 10: 601-620
54. 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; 72: 921-931
55. Brederson JD, Kym PR, Szallasi A,. Targeting TRP channels for pain relief. Eur J Pharmacol 2013; 716: 61-76
56. Binshtok AM, Bean BP, Woolf CJ,. Inhibition of nociceptors by TRPV1-mediated entry of impermeant sodium channel blockers. Nature 2007; 449: 607-610
57. Binshtok AM, Gerner P, Oh SB, et-al. Coapplication of lidocaine and the permanently charged sodium channel blocker QX-314 produces a long-lasting nociceptive blockade in rodents. Anesthesiology 2009; 111: 127-137
58. Zhou C, Liang P, Liu J, et-al. Emulsified isoflurane enhances thermal transient receptor potential vanilloid-1 channel activation-mediated sensory/nociceptive blockade by QX-314. Anesthesiology 2014; 121: 280-289
59. Peters CM, Ririe D, Houle TT, Aschenbrenner CA, Eisenach JC,. Nociceptor-selective peripheral nerve block induces delayed mechanical hypersensitivity and neurotoxicity in rats. Anesthesiology 2014; 120: 976-986
60. Everaerts W, Nilius B, Owsianik G,. The vanilloid transient receptor potential channel TRPV4: from structure to disease. Prog Biophys Mol Biol 2010; 103: 2-17
61. Gevaert T, Vriens J, Segal A, et-al. Deletion of the transient receptor potential cation channel TRPV4 impairs murine bladder voiding. J Clin Invest 2007; 117: 3453-3462
62. Janssen DA, Hoenderop JG, Jansen KC, Kemp AW, Heesakkers JP, Schalken JA,. The mechanoreceptor TRPV4 is localized in adherence junctions of the human bladder urothelium: a morphological study. J Urol 2011; 186: 1121-1127
63. Thorneloe KS, Sulpizio AC, Lin Z, et-al. N-((1S)-1-{[4-((2S)-2-{[(2,4-dichlorophenyl)sulfonyl]amino}-3-hydroxypropanoyl)-1-piperazinyl]carbonyl}-3-methylbutyl)-1-benzothiophene-2-carboxamide (GSK1016790A), a novel and potent transient receptor potential vanilloid 4 channel agonist induces urinary bladder contraction and hyperactivity: part I. J Pharmacol Exp Ther 2008; 326: 432-442
64. Aizawa N, Wyndaele JJ, Homma Y, Igawa Y,. Effects of TRPV4 cation channel activation on the primary bladder afferent activities of the rat. Neurourol Urodyn 2012; 31: 148-155
65. 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 USA 2010; 107: 19084-19089
66. 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; 307: R471-480
67. Landoure G, Zdebik AA, Martinez TL, et-al. Mutations in TRPV4 cause Charcot-Marie-Tooth disease type 2C. Nat Genet 2010; 42: 170-174
68. Ferrer-Montiel A, Fernandez-Carvajal A, Planells-Cases R, et-al. Advances in modulating thermosensory TRP channels. Expert Opin Ther Pat 2012; 22: 999-1017
69. Young JS, Johnston L, Soubrane C, et-al. The passive and active contractile properties of the neurogenic, underactive bladder. BJU Int 2013; 111: 355-361
70. Willette RN, Bao W, Nerurkar S, et-al. Systemic activation of the transient receptor potential vanilloid subtype 4 channel causes endothelial failure and circulatory collapse: part 2. J Pharmacol Exp Ther 2008; 326: 443-452
71. Thorneloe KS, Cheung M, Bao W, et-al. An orally active TRPV4 channel blocker prevents and resolves pulmonary edema induced by heart failure. Sci Transl Med 2012; 4: 159ra48
72. ClinicalTrials.gov. A First Time in Human Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of GSK2798745 in Healthy Subjects and Stable Heart Failure Patients: GlaxoSmithKline, 2014. Available at: http://clinicaltrials.gov/ct2/show/NCT02119260?term=TRPV4&rank=1. Accessed May 2014
73. Voets T, Owsianik G, Nilius B,. TRPM8. Handb Exp Pharmacol 2007; 179: 329-344
74. Mukerji G, Yiangou Y, Corcoran SL, et-al. Cool and menthol receptor TRPM8 in human urinary bladder disorders and clinical correlations. BMC Urol 2006; 6: 6
75. Hayashi T, Kondo T, Ishimatsu M, et-al. Function and expression pattern of TRPM8 in bladder afferent neurons associated with bladder outlet obstruction in rats. Auton Neurosci 2011; 164: 27-33
76. Stein RJ, Santos S, Nagatomi J, et-al. Cool (TRPM8) and hot (TRPV1) receptors in the bladder and male genital tract. J Urol 2004; 172: 1175-1178
77. Tsukimi Y, Mizuyachi K, Yamasaki T, Niki T, Hayashi F,. Cold response of the bladder in guinea pig: involvement of transient receptor potential channel, TRPM8. Urology 2005; 65: 406-410
78. Nomoto Y, Yoshida A, Ikeda S, et-al. Effect of menthol on detrusor smooth-muscle contraction and the micturition reflex in rats. Urology 2008; 72: 701-705
79. 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; 295: F803-810
80. Lindstrom S, Mazieres L,. Effect of menthol on the bladder cooling reflex in the cat. Acta Physiol Scand 1991; 141: 1-10
81. Bors EH, Blinn KA,. Spinal reflex activity from the vesical mucosa in paraplegic patients. AMA Arch Neurol Psychiatry 1957; 78: 339-354
82. Karashima Y, Damann N, Prenen J, et-al. Bimodal action of menthol on the transient receptor potential channel TRPA1. J Neurosci 2007; 27: 9874-9884
83. Mahieu F, Owsianik G, Verbert L, et-al. TRPM8-independent menthol-induced Ca2+ release from endoplasmic reticulum and Golgi. J Biol Chem 2007; 282: 3325-3336
84. Ghei M, Malone-Lee J,. Using the circumstances of symptom experience to assess the severity of urgency in the overactive bladder. J Urol 2005; 174: 972-976
85. Lei Z, Ishizuka O, Imamura T, et-al. Functional roles of transient receptor potential melastatin 8 (TRPM8) channels in the cold stress-induced detrusor overactivity pathways in conscious rats. Neurourol Urodyn 2013; 32: 500-504
86. Kawamura K, Shishido Y, Ohmi M, Inventors; Raqualia Pharma Inc., Original Assignee. Sulfamoyl Benzoic Acid Heterobicyclic Derivatives as trpm8 Antagonists, patent US 20130210858 A1. 15 August 2013
87. Almeida MC, Hew-Butler T, Soriano RN, et-al. Pharmacological blockade of the cold receptor TRPM8 attenuates autonomic and behavioral cold defenses and decreases deep body temperature. J Neurosci 2012; 32: 2086-2099
88. Garcia-Anoveros J, Nagata K,. TRPA1. Handb Exp Pharmacol 2007; 179: 347-362
89. Streng T, Axelsson HE, Hedlund P, et-al. Distribution and function of the hydrogen sulfide-sensitive TRPA1 ion channel in rat urinary bladder. Eur Urol 2008; 53: 391-399
90. Du S, Araki I, Yoshiyama M, Nomura T, Takeda M,. Transient receptor potential channel A1 involved in sensory transduction of rat urinary bladder through C-fiber pathway. Urology 2007; 70: 826-831
91. Andrade EL, Ferreira J, Andre E, Calixto JB,. Contractile mechanisms coupled to TRPA1 receptor activation in rat urinary bladder. Biochem Pharmacol 2006; 72: 104-114
92. Weinhold P, Gratzke C, Streng T, Stief C, Andersson KE, Hedlund P,. TRPA1 receptor induced relaxation of the human urethra involves TRPV1 and cannabinoid receptor mediated signals, and cyclooxygenase activation. J Urol 2010; 183: 2070-2076
93. Meseguer V, Alpizar YA, Luis E, et-al. TRPA1 channels mediate acute neurogenic inflammation and pain produced by bacterial endotoxins. Nat Commun 2014; 5: 3125
94. Uvin P, Franken J, Boudes M, et-al. The bladder-cooling reflex is a local phenomenon, mediated by TRPA1. Neurourol Urodyn 2013; 32: 572-573
95. EU Clinical Trials Register. A Phase 2a, Multi-Centre, Randomised, Double-Blind, Parallel Group, Placebo-Controlled Study to Evaluate Efficacy, Safety and Tolerability of Inhaled GRC 17536, Administered for 4 Weeks, in Patients with refractory chronic cough (internet) (Place unknown): Glenmark Pharmaceuticals SA, 2013. Available at: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2013-002728-17. Accessed May 2014
96. Andrade EL, Forner S, Bento AF, et-al. TRPA1 receptor modulation attenuates bladder overactivity induced by spinal cord injury. Am J Physiol Renal Physiol 2011; 300: F1223-1234
97. Deberry JJ, Schwartz ES, Davis BM,. TRPA1 mediates bladder hyperalgesia in a mouse model of cystitis. Pain 2014; 155: 1280-1287
98. Caprodossi S, Lucciarini R, Amantini C, et-al. Transient receptor potential vanilloid type 2 (TRPV2) expression in normal urothelium and in urothelial carcinoma of human bladder: correlation with the pathologic stage. Eur Urol 2008; 54: 612-620
99. Smith AC, Parajuli SP, Hristov KL, et-al. TRPM4 channel: a new player in urinary bladder smooth muscle function in rats. Am J Physiol Renal Physiol 2013; 304: F918-929