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Distribution and function of the endocannabinoid system in the rat and human bladder

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Abstract

Introduction and hypothesis

Our aim was to compare expression and distribution of cannabinoid receptors CB1 and CB2, transient receptor potential vanilloid receptor 1 (TRPV1), and modulating enzymes in human and rat bladder. We also evaluated effects of cannabinoid agonists (ACEA, agonist of CB1; GP1A, agonist of CB2) on contractile responses of rat bladder strips.

Methods

Distribution and expression of CB1, CB2 and TRPV1 receptors and enzymes fatty acid amide hydrolase (FAAH) and N-acyl phosphatidylethanolamine-hydrolyzing phospholipase D (NAPE-PLD) was studied using immunohistochemistry and immunoblotting on human and Wistar rat bladders. The effects of cannabinoid agonists on contractile responses of isolated rat bladder strips to electrical-field stimulation (EFS) or carbachol-evoked responses were determined.

Results

Immunoreactivity for CB1 and TRPV1 receptors and FAAH and NAPE-PLD was present in the bladder of both species. CB1 proteins were of different sizes in rat (57 kDa) and human (40 kDa) bladder. CB2 (45 kDa in both species) immunolocalised to both urothelium and detrusor muscle in human bladder but only to detrusor muscle in rat. FAAH proteins were found at 55 kDa for both species. Rat NAPE-PLD protein (44 kDa) was similar in size to that in human bladder (45 kDa). TRPV1 proteins were found at 104 kDa in both species. ACEA (10−4 M) attenuated bladder contractions by 35 ± 5.4 % (p < 0.001); GP1a had no effect despite the EC50 values for the carbachol dose–response curves for both agonists being significantly shifted to the right.

Conclusions

The endocannabinoid system is functionally expressed in both species, with CB1 receptors showing both pre- and postsynaptic inhibitory effects on rat bladder contraction, whereas CB2 acts only postsynaptically.

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References

  1. Haylen BT, de Ridder D, Freeman RM et al (2010) An International Urogynaecological Association (IUGA)/International Continence Society (ICS) joint report on the terminology for female pelvic floor dysfunction. Int Urogynecol J Pelvic Floor 21(1):5–26

    Article  Google Scholar 

  2. Irwin DE, Milsom I, Hunskaar S, Reilly K, Kopp Z, Herschorn S et al (2006) Population-based survey of urinary incontinence, overactive bladder, and other lower urinary tract symptoms in five countries: results of the EPIC study. Eur Urol 50:1306–1314, discussion 1314–5

    Article  PubMed  Google Scholar 

  3. Freeman RM, Adekanmi O, Waterfield MR, Waterfield AE, Wright D, Zajicek J (2006) The effect of cannabis on urge incontinence in patients with multiple sclerosis: a multicentre, randomised placebo-controlled trial (CAMS-LUTS). Int Urogynecol J Pelvic Floor Dysfunct 17:636–641

    Article  PubMed  CAS  Google Scholar 

  4. Amar B (2006) Cannabinoids in medicine: a review of their therapeutic potential. J Ethnopharmacol 105:1–25

    Article  PubMed  Google Scholar 

  5. Gratzke C, Streng T, Park A, Christ G, Stief CG, Hedlund P et al (2009) Distribution and function of cannabinoid receptors 1 and 2 in the rat, monkey and human bladder. J Urol 181:1939–1948

    Article  PubMed  CAS  Google Scholar 

  6. Tyagi V, Philips BJ, Su R, Smaldone MC, Erickson VL, Chancellor MB et al (2009) Differential expression of functional cannabinoid receptors in human bladder detrusor and urothelium. J Urol 181:1932–1938

    Article  PubMed  CAS  Google Scholar 

  7. Strittmatter F, Gandaglia G, Benigni F, Bettiga A, Rigatti P, Montorsi F et al (2012) Expression of fatty acid amide hydrolase (FAAH) in human, mouse, and rat urinary bladder and effects of FAAH inhibition on bladder function in awake rats. Eur Urol 61:98–106

    Article  PubMed  CAS  Google Scholar 

  8. Egertová M, Simon GM, Cravatt BF, Elphick MR (2008) Localization of N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD) expression in mouse brain: a new perspective on N-acylethanolamines as neural signaling molecules. J Comp Neurol 506:604–615

    Article  PubMed  Google Scholar 

  9. Tsou K, Nogueron MI, Muthian S, Sañudo-Pena MC, Hillard CJ, Deutsch DG et al (1998) Fatty acid amide hydrolase is located preferentially in large neurons in the rat central nervous system as revealed by immunohistochemistry. Neurosci Lett 254:137–140

    Article  PubMed  CAS  Google Scholar 

  10. Geirsson G, Fall M, Sullivan L (1995) Clinical and urodynamic effects of intravesical capsaicin treatment in patients with chronic traumatic spinal detrusor hyperreflexia. J Urol 154:1825–1829

    Article  PubMed  CAS  Google Scholar 

  11. Birder LA, Kanai AJ, de Groat WC, Kiss S, Nealen ML, Burke NE et al (2001) Vanilloid receptor expression suggests a sensory role for urinary bladder epithelial cells. Proc Natl Acad Sci U S A 98:13396–13401

    Article  PubMed  CAS  Google Scholar 

  12. Hayn MH, Ballesteros I, de Miguel F, Coyle CH, Tyagi S, Yoshimura N et al (2008) Functional and immunohistochemical characterization of CB1 and CB2 receptors in rat bladder. Urology 72:1174–1178

    Article  PubMed  Google Scholar 

  13. Gratzke C, Streng T, Stief CG, Downs TR, Alroy I, Rosenbaum JS et al (2010) Effects of cannabinor, a novel selective cannabinoid 2 receptor agonist, on bladder function in normal rats. Eur Urol 57:1093–1100

    Article  PubMed  Google Scholar 

  14. Marquéz L, Suárez J, Iglesias M, Bermudez-Silva FJ, Rodríguez de Fonseca F, Andreu M (2009) Ulcerative colitis induces changes on the expression of the endocannabinoid system in the human colonic tissue. PLoS One 4:e6893

    Article  PubMed  Google Scholar 

  15. Ueda N, Puffenbarger RA, Yamamoto S, Deutsch DG (2000) The fatty acid amide hydrolase (FAAH). Chem Phys Lipids 108:107–121

    Article  PubMed  CAS  Google Scholar 

  16. Katayama K, Ueda N, Kurahashi Y, Suzuki H, Yamamoto S, Kato I (1997) Distribution of anandamide amidohydrolase in rat tissues with special reference to small intestine. Biochim Biophys Acta 1347:212–218

    Article  PubMed  CAS  Google Scholar 

  17. Desarnaud F, Cadas H, Piomelli D (1995) Anandamide amidohydrolase activity in rat brain microsomes. Identification and partial characterization. J Biol Chem 270:6030–6035

    Article  PubMed  CAS  Google Scholar 

  18. Giang DK, Cravatt BF (1997) Molecular characterization of human and mouse fatty acid amide hydrolases. Proc Natl Acad Sci 94:2238

    Article  PubMed  CAS  Google Scholar 

  19. Storr MA, Keenan CM, Emmerdinger D, Zhang H, Yüce B, Sibaev A et al (2008) Targeting endocannabinoid degradation protects against experimental colitis in mice: involvement of CB1 and CB2 receptors. J Mol Med 86:925–936

    Article  PubMed  CAS  Google Scholar 

  20. Dinis P, Charrua A, Avelino A, Cruz F (2004) Intravesical resiniferatoxin decreases spinal c-fos expression and increases bladder volume to reflex micturition in rats with chronic inflamed urinary bladders. BJU Int 94:153–157

    Article  PubMed  Google Scholar 

  21. Dinis P, Charrua A, Avelino A, Yaqoob M, Bevan S, Nagy I et al (2004) 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 24:11253–11263

    Article  PubMed  CAS  Google Scholar 

  22. Ishizuka O, Igawa Y, Mattiasson A, Andersson KE (1994) Capsaicin-induced bladder hyperactivity in normal conscious rats. J Urol 152:525–530

    PubMed  CAS  Google Scholar 

  23. Lazzeri M, Vannucchi MG, Zardo C, Spinelli M, Beneforti P, Turini D et al (2004) Immunohistochemical evidence of vanilloid receptor 1 in normal human urinary bladder. Eur Urol 46:792–798

    Article  PubMed  CAS  Google Scholar 

  24. Brady CM, Apostolidis AN, Harper M, Yiangou Y, Beckett A, Jacques TS et al (2004) 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 93:770–776

    Article  PubMed  CAS  Google Scholar 

  25. Ost D, Roskams T, Van Der Aa F, De Ridder D (2002) Topography of the vanilloid receptor in the human bladder: more than just the nerve fibers. J Urol 168:293–297

    Article  PubMed  Google Scholar 

  26. Martin RS, Luong LA, Welsh NJ, Eglen RM, Martin GR, MacLennan SJ (2000) Effects of cannabinoid receptor agonists on neuronally-evoked contractions of urinary bladder tissues isolated from rat, mouse, pig, dog, monkey and human. Br J Pharmacol 129:1707–1715

    Article  PubMed  CAS  Google Scholar 

  27. Pertwee RG, Fernando SR (1996) Evidence for the presence of cannabinoid CB1 receptors in mouse urinary bladder. Br J Pharmacol 118:2053–2058

    Article  PubMed  CAS  Google Scholar 

  28. Walczak JS, Price TJ, Cervero F (2009) Cannabinoid CB1 receptors are expressed in the mouse urinary bladder and their activation modulates afferent bladder activity. Neuroscience 159:1154–1163

    Article  PubMed  CAS  Google Scholar 

  29. Birder LA (2010) Urothelial signaling. Auton Neurosci 153:33–40

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We want to thank Dr. Tim Marczylo for his guidance with the experiments and for his suggestions towards the manuscript.

Funding

Wellbeing of Women

Conflicts of interest

None.

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Authors and Affiliations

  1. Prolapse and Incontinence Research Group, University of Leicester, Leicester, UK

    Evangelia Bakali, Ruth A. Elliott & Douglas G. Tincello

  2. Endocannabinoid Research Group, Reproductive Sciences Section, Department of Cancer Studies & Molecular Medicine, University of Leicester, Leicester, UK

    Anthony H. Taylor, Jon Willets & Justin C. Konje

  3. Department of Cancer Studies & Molecular Medicine, Reproductive Sciences Section, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, PO Box 65, Leicester, Leicestershire, LE2 7LX, UK

    Douglas G. Tincello

Authors
  1. Evangelia Bakali
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  2. Ruth A. Elliott
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  3. Anthony H. Taylor
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  4. Jon Willets
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  6. Douglas G. Tincello
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Correspondence to Douglas G. Tincello.

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Bakali, E., Elliott, R.A., Taylor, A.H. et al. Distribution and function of the endocannabinoid system in the rat and human bladder. Int Urogynecol J 24, 855–863 (2013). https://doi.org/10.1007/s00192-012-1954-1

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  • DOI: https://doi.org/10.1007/s00192-012-1954-1

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