Skip to main content

Advertisement

SpringerLink
Log in

Cannabinoid receptor expression in the bladder is altered in detrusor overactivity

  • Original Article
  • Published:
International Urogynecology Journal Aims and scope Submit manuscript

Abstract

Introduction

Immunohistochemical (IHC) evidence shows that cannabinoid receptors (CB) are expressed in human bladders and cannabinoid agonists are known to inhibit detrusor contractility. However, the mechanism for this inhibition remains unknown. In addition, the role of CB in detrusor overactivity (DO) is under-investigated. The aim of this study was to compare CB expression in normal and DO human bladders and to further characterise these receptors.

Methods

Polymer chain reaction (PCR) was used to detect differences in CB transcripts in bladder samples. Differences in CB protein expression was assessed by IHC. Immunofluorescence (IF) was used to evaluate co-localisation of CB with nerve fibres. Receptor density and binding affinity were measured using the cannabinoid radioligand [3H]-CP-55,940.

Results

There were higher levels of CB1 transcripts in the urothelium of patients with DO and lower levels in the detrusor, compared with normal bladders. Radioligand binding revealed CB density of 421 ± 104 fmol/mg protein in normal human bladders. IHC confirmed these findings at the protein level. IF staining demonstrated co-localisation of CB1 with choline acetyltransferase-(ChAT)-positive nerves in the detrusor and co-localisation with PGP9.5 in both urothelium and detrusor. CB2 was co-localised with both ChAT and PGP9.5 in the urothelium and the detrusor.

Conclusions

Cannabinoid receptor expression is reduced in the detrusor of patients with DO, which may play a role in the pathophysiology of the disease. Co-localisation of CB receptors with cholinergic nerves may suggest that CB1, being localised on pre- and postsynaptic terminals, could influence neurotransmitter release. Our findings suggest the potential role of cannabinoid agonists in overactive bladder pharmacotherapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Kavia RB, De Ridder D, Constantinescu CS, Stott CG, Fowler CJ (2010) Randomized controlled trial of Sativex to treat detrusor overactivity in multiple sclerosis. Mult Scler 16:1349–1359

    Article  PubMed  CAS  Google Scholar 

  2. Freeman RM, Adekanmi O, Waterfield MR, Waterfield AE, Wright D et al (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 

  3. Ahn K, Johnson DS, Cravatt BF (2009) Fatty acid amide hydrolase as a potential therapeutic target for the treatment of pain and CNS disorders. Expert Opin Drug Discovery 4:763–784

    Article  CAS  Google Scholar 

  4. Bakali E, Elliott RA, Taylor AH, Willets J, Konje JC et al (2013) Distribution and function of the endocannabinoid system in the rat and human bladder. Int Urogynecol J Pelvic Floor Dysfunct 24:855–863

    Article  Google Scholar 

  5. Gratzke C, Streng T, Park A, Christ G, Stief CG 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 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. Hayn MH, Ballesteros I, de Miguel F, Coyle CH, Tyagi S et al (2008) Functional and immunohistochemical characterization of CB1 and CB2 receptors in rat bladder. Urology 72:1174–1178

    Article  PubMed  Google Scholar 

  8. Mukerji G, Yiangou Y, Agarwal SK, Anand P (2010) Increased cannabinoid receptor 1-immunoreactive nerve fibers in overactive and painful bladder disorders and their correlation with symptoms. Urology 75:1514.e15–1514.e20

    Article  Google Scholar 

  9. 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 

  10. Martin RS, Luong LA, Welsh NJ, Eglen RM, Martin GR et al (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  PubMed Central  Google Scholar 

  11. 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  PubMed Central  Google Scholar 

  12. Gratzke C, Streng T, Stief CG, Downs TR, Alroy I 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 

  13. Hiragata S, Ogawa T, Hayashi Y, Tyagi P, Seki S et al (2007) Effects of IP-751, ajulemic acid, on bladder overactivity induced by bladder irritation in rats. Urology 70:202–208

    Article  PubMed  Google Scholar 

  14. Dmitrieva N, Berkley KJ (2002) Contrasting effects of WIN 55212–2 on motility of the rat bladder and uterus. J Neurosci 22:7147–7153

    PubMed  CAS  Google Scholar 

  15. Walczak JS, Cervero F (2011) Local activation of cannabinoid CB1 receptors in the urinary bladder reduces the inflammation-induced sensitization of bladder afferents. Mol Pain 7:31

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  16. Amaya F, Shimosato G, Kawasaki Y, Hashimoto S, Tanaka Y et al (2006) Induction of CB1 cannabinoid receptor by inflammation in primary afferent neurons facilitates antihyperalgesic effect of peripheral CB1 agonist. Pain 124:175–183

    Article  PubMed  CAS  Google Scholar 

  17. Hedlund P (2014) Cannabinoids and the endocannabinoid system in lower urinary tract function and dysfunction. Neurourol Urodyn 33:46–53

    Article  PubMed  CAS  Google Scholar 

  18. Gillespie JI, Markerink-van Ittersum M, De Vente J (2006) Interstitial cells and cholinergic signalling in the outer muscle layers of the guinea-pig bladder. BJU Int 97:379–385

    Article  PubMed  CAS  Google Scholar 

  19. Haylen BT, de Ridder D, Freeman RM, Swift SE, Berghmans B et al (2010) An International Urogynecological Association (IUGA)/International Continence Society (ICS) joint report on the terminology for female pelvic floor dysfunction. Neurourol Urodyn 29:4–20

    PubMed  Google Scholar 

  20. Lowry O, Rosebrough N, Farr A, Randall R (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275

    PubMed  CAS  Google Scholar 

  21. Brighton PJ, McDonald J, Taylor AH, Challiss RA, Lambert DG et al (2009) Characterization of anandamide-stimulated cannabinoid receptor signaling in human ULTR myometrial smooth muscle cells. Mol Endocrinol 23:1415–1427

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  22. Thomas A, Ross RA, Saha B, Mahadevan A, Razdan RK et al (2004) 6“-Azidohex-2”-yne-cannabidiol: a potential neutral, competitive cannabinoid CB1 receptor antagonist. Eur J Pharmacol 487:213–221

    Article  PubMed  CAS  Google Scholar 

  23. Katagigiotis S, Kavia R, Gonzales G, Dimitriadis F, Ioannidis E et al (2012) Is there a local bladder effect of oral cannabinoid agonists? Eur Urol Suppl 11:e370–e370a.

    Article  Google Scholar 

  24. Merriam FV, Wang ZY, Guerios SD, Bjorling DE (2008) Cannabinoid receptor 2 is increased in acutely and chronically inflamed bladder of rats. Neurosci Lett 445:130–134

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  25. Gong JP, Onaivi ES, Ishiguro H, Liu QR, Tagliaferro PA et al (2006) Cannabinoid CB2 receptors: immunohistochemical localization in rat brain. Brain Res 1071:10–23

    Article  PubMed  CAS  Google Scholar 

  26. Stanley C, O’Sullivan SE (2014) Vascular targets for cannabinoids: animal and human studies. Br J Pharmacol 171:1361–1378

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  27. Veress G, Meszar Z, Muszil D, Avelino A, Matesz K et al (2013) Characterisation of cannabinoid 1 receptor expression in the perikarya, and peripheral and spinal processes of primary sensory neurons. Brain Struct Funct 218:733–750

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  28. Wilson RI, Nicoll RA (2001) Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses. Nature 410:588–592

    Article  PubMed  CAS  Google Scholar 

  29. Gatley SJ, Lan R, Pyatt B, Gifford AN, Volkow ND et al (1997) Binding of the non-classical cannabinoid CP 55,940, and the diarylpyrazole AM251 to rodent brain cannabinoid receptors. Life Sci 61:PL191–PL197

    Article  CAS  Google Scholar 

  30. Hill TD, Cascio MG, Romano B, Duncan M, Pertwee RG et al (2013) Cannabidivarin-rich cannabis extracts are anticonvulsant in mouse and rat via a CB1 receptor-independent mechanism. Br J Pharmacol 170:679–692

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  31. Bisogno T, Howell F, Williams G, Minassi A, Cascio MG et al (2003) Cloning of the first sn1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signaling in the brain. J Cell Biol 163:463–468

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  32. Dinh TP, Carpenter D, Leslie FM, Freund TF, Katona I et al (2002) Brain monoglyceride lipase participating in endocannabinoid inactivation. Proc Natl Acad Sci U S A 99:10819–10824

    Article  PubMed  CAS  PubMed Central  Google Scholar 

Download references

Conflicts of interest

Professor Lambert is an administration director for the British Journal of Anaesthesia.

Author information

Authors and Affiliations

  1. Reproductive Sciences Section, Health Sciences, University of Leicester, Leicester, UK

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

  2. Department of Cardiovascular Sciences, University of Leicester, Leicester, UK

    John McDonald & David G. Lambert

  3. Department of Health Sciences, Leicester Royal Infirmary, University of Leicester, Robert Kilpatrick Clinical Sciences Building, Leicester, LE2 7LX, UK

    Evangelia Bakali

Authors
  1. Evangelia Bakali
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John McDonald
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ruth A. Elliott
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. David G. Lambert
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Douglas G. Tincello
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Evangelia Bakali.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bakali, E., McDonald, J., Elliott, R.A. et al. Cannabinoid receptor expression in the bladder is altered in detrusor overactivity. Int Urogynecol J 27, 129–139 (2016). https://doi.org/10.1007/s00192-015-2802-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00192-015-2802-x

Keywords

Search

Navigation