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Current Understanding of Cannabinoids and Detrusor Overactivity

  • Overactive Bladder (U Lee, Section Editor)
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Abstract

Purpose of Review

The purpose of this review is to review current studies of cannabinoids and the urinary bladder.

Recent Findings

Cannabinoids have been identified in the urinary bladder and are purported to play a modulatory role in detrusor overactivity (DO) as there is a change in the expression of cannabinoid receptors (CBR) in these patients compared to healthy controls. Studies using knock-out mice suggest sensory urodynamic endpoints can be modified by activation of the CBR. Clinical studies demonstrated that Cannabis improves urgency in patients with neurogenic DO.

Summary

CBR are involved in micturition at both peripheral and CNS sites. CBR expressed in afferent fibre endings in the urothelium could influence bladder function. CBR agonists may be useful for future treatment of DO as there is altered CBR expression in these bladders. In addition, FAAH-2 has been localised in human bladder and future studies may show that this enzyme has a role in bladder dysfunction.

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References

Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. Gratzke C, Streng T, Stief CG, Downs TR, Alroy I, Rosenbaum JS, et al. Effects of cannabinor, a novel selective cannabinoid 2 receptor agonist, on bladder function in normal rats. Eur Urol. 2010;57:1093–100.

    Article  CAS  PubMed  Google Scholar 

  2. Mukerji G, Yiangou Y, Agarwal SK, Anand P. Increased cannabinoid receptor 1-immunoreactive nerve fibers in overactive and painful bladder disorders and their correlation with symptoms. Urology. 2010;75:1514. e15-20.

    Article  PubMed  Google Scholar 

  3. •• Bakali E, McDonald J, Elliott RA, Lambert DG, Tincello DG. Cannabinoid receptor expression in the bladder is altered in detrusor overactivity. Int Urogynecol J Pelvic Floor Dysfunct. 2016;27:129–39. The first study to compare cannabinoid receptor expression in patients with detrusor overactivity and healthy controls. They found CB1 receptor was significantly upregulated by 2.8-fold in urothelium of DO samples and downregulated by 3.2-fold in the detrusor of DO samples compared to normal bladder samples.

  4. Brady CM, Apostolidis AN, Harper M, Yiangou Y, Beckett A, Jacques TS, 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;93:770–6.

    Article  CAS  PubMed  Google Scholar 

  5. Freeman RM, Adekanmi O, Waterfield MR, Waterfield AE, Wright D, Zajicek J. 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. 2006;17:636–41.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  7. Mechoulam R. Chapter 1: the pharmacohistory of cannabis sativa. In: Mechoulam R, editor. Cannabinoids as therapeutic agents. Boca Raton: CRC Press; 1986.

    Google Scholar 

  8. Samuelsson G. Drugs of natural origin: a treatise of pharmacognosy. Stockholm: Swedish Academy of Pharmaceutical Sciences; 2009.

    Google Scholar 

  9. Abel EL. Marihuana, the first twelve thousand years. New York: Plenum press; 1980.

    Google Scholar 

  10. O’Shaughnessy WB. On the preparations of the indian hemp, or gunjah: Cannabis indica their effects on the animal system in health, and their utility in the treatment of tetanus and other convulsive diseases. Provincial Med J Retrospect Med Sci. 1843;5:363.

    Google Scholar 

  11. Ben Amar M. Cannabinoids in medicine: a review of their therapeutic potential. J Ethnopharmacol. 2006;105:1–25.

    Article  CAS  PubMed  Google Scholar 

  12. Devane WA, Dysarz FA, Johnson MR, Melvin LS, Howlett AC. Determination and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol. 1988;34:605–13.

    CAS  PubMed  Google Scholar 

  13. Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI. Structure of a cannabinoid receptor and functional expression of the cloned cdna. Nature. 1990;346:561–4.

    Article  CAS  PubMed  Google Scholar 

  14. Pertwee RG, Ross RA. Cannabinoid receptors and their ligands. Prostaglandins Leukot Essent Fat Acids. 2002;66:101.

    Article  CAS  Google Scholar 

  15. Pertwee RG. Cannabinoid receptors and their ligands. Tocris Rev. 2001;16:1–8.

    Google Scholar 

  16. Munro S, Thomas KL, Abu-Shaar M. Molecular characterization of a peripheral receptor for cannabinoids. Nature. 1993;365:61–5.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  18. Blankman JL, Cravatt BF. Chemical probes of endocannabinoid metabolism. Pharmacol Rev. 2013;65:849–71.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Bakali E, Elliott RA, Taylor AH, Willets J, Konje JC, Tincello DG. Distribution and function of the endocannabinoid system in the rat and human bladder. Int Urogynecol J Pelvic Floor Dysfunct. 2013;24:855–63.

    Article  Google Scholar 

  20. Füllhase C, Russo A, Castiglione F, Benigni F, Campeau L, Montorsi F, et al. Spinal cord FAAH in normal micturition control and bladder overactivity in awake rats. J Urol. 2013;189:2364–70.

    Article  PubMed  Google Scholar 

  21. •• Füllhase C, Schreiber A, Giese A, Schmidt M, Montorsi F, Gratzke C, et al. Spinal neuronal cannabinoid receptors mediate urodynamic effects of systemic fatty acid amide hydrolase (FAAH) inhibition in rats. Neurourol Urodyn. 2016;35:464–70. Intrathecal CB1 and CB2 antagonists were able to modify normal bladder function in conscious rats and these effects were reversed by OEA, an FAAH inhibitor. These effects indicate that the effects of endogenous agonists on cannabinoid receptors in sacral neurons are involved in regulating sensory functions of the bladder.

  22. Aizawa N, Gandaglia G, Hedlund P, Fujimura T, Fukuhara H, Montorsi F, et al. URB937, a peripherally restricted inhibitor for fatty acid amide hydrolase, reduces prostaglandin E2 -induced bladder overactivity and hyperactivity of bladder mechano-afferent nerve fibres in rats. BJU Int. 2016;117:821–8.

    Article  CAS  PubMed  Google Scholar 

  23. Pertwee RG. Pharmacological actions of cannabinoids. Cannabinoids 2005:1-51.

  24. Capasso R, Orlando P, Pagano E, Aveta T, Buono L, Borrelli F, et al. Palmitoylethanolamide normalizes intestinal motility in a model of post-inflammatory accelerated transit: involvement of CB1 receptors and TRPV1 channels. Br J Pharmacol. 2014;171:4026–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. MacNaughton WK, Van Sickle MD, Keenan CM, Cushing K, Mackie K, Sharkey KA. Distribution and function of the cannabinoid-1 receptor in the modulation of ion transport in the guinea pig ileum: relationship to capsaicin-sensitive nerves. Am J Physiol Gastrointest Liver Physiol. 2004;286:G863–71.

    Article  CAS  PubMed  Google Scholar 

  26. Avelino A, Cruz F. TRPV1 (vanilloid receptor) in the urinary tract: expression, function and clinical applications. Naunyn Schmiedeberg’s Arch Pharmacol. 2006;373:287–99.

    Article  CAS  Google Scholar 

  27. Tyagi V, Philips BJ, Su R, Smaldone MC, Erickson VL, Chancellor MB, et al. Differential expression of functional cannabinoid receptors in human bladder detrusor and urothelium. J Urol. 2009;181:1932–8.

    Article  CAS  PubMed  Google Scholar 

  28. Gratzke C, Streng T, Park A, Christ G, Stief CG, Hedlund P, et al. Distribution and function of cannabinoid receptors 1 and 2 in the rat, monkey and human bladder. J Urol. 2009;181:1939–48.

    Article  CAS  PubMed  Google Scholar 

  29. Li Y, Sun Y, Zhang Z, Feng X, Meng H, Li S, et al. Cannabinoid receptors 1 and 2 are associated with bladder dysfunction in an experimental diabetic rat model. BJU Int. 2013;112:E143–50.

    Article  CAS  PubMed  Google Scholar 

  30. Hayn MH, Ballesteros I, de Miguel F, Coyle CH, Tyagi S, Yoshimura N, et al. Functional and immunohistochemical characterization of CB1 and CB2 receptors in rat bladder. Urology. 2008;72:1174–8.

    Article  PubMed  Google Scholar 

  31. Walczak JS, Price TJ, Cervero F. Cannabinoid CB1 receptors are expressed in the mouse urinary bladder and their activation modulates afferent bladder activity. Neuroscience. 2009;31:1154–63.

    Article  Google Scholar 

  32. Veress G, Meszar Z, Muszil D, Avelino A, Matesz K, Mackie K, et al. Characterisation of cannabinoid 1 receptor expression in the perikarya, and peripheral and spinal processes of primary sensory neurons. Brain Struct Funct. 2013;218:733–50.

    Article  CAS  PubMed  Google Scholar 

  33. Merriam FV, Wang ZY, Guerios SD, Bjorling DE. Cannabinoid receptor 2 is increased in acutely and chronically inflamed bladder of rats. Neurosci Lett. 2008;445:130–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Wang ZY, Wang P, Bjorling DE. Activation of cannabinoid receptor 2 inhibits experimental cystitis. Am J Physiol Regul Integr Comp Physiol. 2013;304:R846–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Strittmatter F, Gandaglia G, Benigni F, Bettiga A, Rigatti P, Montorsi F, et al. 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. 2012;61:98–106.

    Article  CAS  PubMed  Google Scholar 

  36. Cravatt BF, Saghatelian A, Hawkins EG, Clement AB, Bracey MH, Lichtman AH. Functional disassociation of the central and peripheral fatty acid amide signaling systems. Proc Natl Acad Sci U S A. 2004;101:10821–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Wei BQ, Mikkelsen TS, McKinney MK, Lander ES, Cravatt BF. A second fatty acid amide hydrolase with variable distribution among placental mammals. J Biol Chem. 2006;281:36569–78.

    Article  CAS  PubMed  Google Scholar 

  38. Pacher P, Bátkai S, Kunos G. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev. 2006;58:389–462.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Pertwee RG, Howlett AC, Abood ME, Alexander SP, Di Marzo V, Elphick MR, et al. International union of basic and clinical pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB1 and CB2. Pharmacol Rev. 2010;62:588–631.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Hiragata S, Ogawa T, Hayashi Y, Tyagi P, Seki S, Nishizawa O, et al. Effects of IP-751, ajulemic acid, on bladder overactivity induced by bladder irritation in rats. Urology. 2007;70:202–8.

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Suzuki Y, Inoue T, Ra C. L-type ca2+ channels: a new player in the regulation of ca2+ signaling, cell activation and cell survival in immune cells. Mol Immunol. 2010;47:640–8.

    Article  CAS  PubMed  Google Scholar 

  43. Wegener JW, Schulla V, Lee TS, Koller A, Feil S, Feil R, et al. An essential role of cav1.2 l-type calcium channel for urinary bladder function. FASEB J. 2004;18:1159–61.

    CAS  PubMed  Google Scholar 

  44. Gebremedhin D, Lange AR, Campbell WB, Hillard CJ, Harder DR. Cannabinoid CB1 receptor of cat cerebral arterial muscle functions to inhibit l-type ca2+ channel current. Am J Physiol. 1999;276:H2085–93.

    CAS  PubMed  Google Scholar 

  45. Pertwee R, Griffin G, Fernando S, Li X, Hill A, Makriyannis A. AM630, a competitive cannabinoid receptor antagonist. Life Sci. 1995;56:1949–55.

    Article  CAS  PubMed  Google Scholar 

  46. Gatley SJ, Lan R, Pyatt B, Gifford AN, Volkow ND, Makriyannis A. Binding of the non-classical cannabinoid CP 55,940, and the diarylpyrazole AM251 to rodent brain cannabinoid receptors. Life Sci. 1997;61:PL 191–7.

    Article  CAS  Google Scholar 

  47. Jaggar SI, Sellaturay S, Rice ASC. The endogenous cannabinoid anandamide, but not the CB2 ligand palmitoylethanolamide, prevents the viscero-visceral hyper-reflexia associated with inflammation of the rat urinary bladder. Neurosci Lett. 1998;253:123–6.

    Article  CAS  PubMed  Google Scholar 

  48. Dmitrieva N, Berkley KJ. Contrasting effects of WIN 55212-2 on motility of the rat bladder and uterus. J Neurosci. 2002;22:7147–53.

    CAS  PubMed  Google Scholar 

  49. Aizawa N, Hedlund P, Füllhase C, Ito H, Homma Y, Igawa Y. Inhibition of peripheral FAAH depresses activities of bladder mechanosensitive nerve fibers of the rat. J Urol. 2014;192:956–63.

    Article  CAS  PubMed  Google Scholar 

  50. Gandaglia G, Strittmatter F, La Croce G, Benigni F, Bettiga A, Castiglione F, et al. The fatty acid amide hydrolase inhibitor oleoyl ethyl amide counteracts bladder overactivity in female rats. Neurourol Urodyn. 2014;33:1251–8.

    Article  CAS  PubMed  Google Scholar 

  51. Campeau L, Füllhase C, Sawada N, Gratzke C, Hedlund P, Howlett AC, et al. Characterization of bladder function in a cannabinoid receptor type 2 knockout mouse in vivo and in vitro. Neurourol Urodyn. 2014;33:566–70.

    Article  CAS  PubMed  Google Scholar 

  52. Füllhase C, Campeau L, Sibaev A, Storr M, Hennenberg M, Gratzke C, et al. Bladder function in a cannabinoid receptor type 1 knockout mouse. BJU Int. 2014;113:144–51.

    Article  PubMed  Google Scholar 

  53. Wilson RI, Nicoll RA. Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses. Nature. 2001;410:588–92.

    Article  CAS  PubMed  Google Scholar 

  54. Bridges D, Rice AS, Egertová M, Elphick MR, Winter J, Michael GJ. Localisation of cannabinoid receptor 1 in rat dorsal root ganglion using in situ hybridisation and immunohistochemistry. Neuroscience. 2003;119:803–12.

    Article  CAS  PubMed  Google Scholar 

  55. Mitrirattanakul S, Ramakul N, Guerrero AV, Matsuka Y, Ono T, Iwase H, et al. Site-specific increases in peripheral cannabinoid receptors and their endogenous ligands in a model of neuropathic pain. Pain. 2006;126:102–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Bakali E, Mbaki Y, Lambert DG, Elliott RA, Mason R, Tincello DG. Effects of cannabinoid receptor activation by CP55,940 on normal bladder function and irritation-induced bladder overactivity in non-awake anaesthetised rats. Int Urogynecol J Pelvic Floor Dysfunct. 2016;27:1393–400.

    Article  Google Scholar 

  57. Birder L, Andersson KE. Urothelial signaling. Physiol Rev. 2013;93:653–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Andersson KE, Arner A. Urinary bladder contraction and relaxation: physiology and pathophysiology. Physiol Rev. 2004;84:935–86.

    Article  CAS  PubMed  Google Scholar 

  59. Lowe EM, Anand P, Terenghi G, Williams-Chestnut RE, Sinicropi DV, Osborne JL. Increased nerve growth factor levels in the urinary bladder of women with idiopathic sensory urgency and interstitial cystitis. Br J Urol. 1997;79:572–7.

    Article  CAS  PubMed  Google Scholar 

  60. Zvara P, Vizzard MA. Exogenous overexpression of nerve growth factor in the urinary bladder produces bladder overactivity and altered micturition circuitry in the lumbosacral spinal cord. BMC Physiol. 2007;28:7–9.

    Google Scholar 

  61. Liu H-T, Kuo H-C. Urinary nerve growth factor levels are elevated in patients with overactive bladder and do not significantly increase with bladder distention. Neurourol Urodyn. 2009;28:78–81.

    Article  PubMed  Google Scholar 

  62. Liu HT, Tyagi P, Chancellor MB, Kuo HC. Urinary nerve growth factor level is increased in patients with interstitial cystitis/bladder pain syndrome and decreased in responders to treatment. BJU Int. 2009;104:1476–81.

    Article  CAS  PubMed  Google Scholar 

  63. Amaya F, Shimosato G, Kawasaki Y, Hashimoto S, Tanaka Y, Ji RR, et al. Induction of CB1 cannabinoid receptor by inflammation in primary afferent neurons facilitates antihyperalgesic effect of peripheral CB1 agonist. Pain. 2006;124:175–83.

    Article  CAS  PubMed  Google Scholar 

  64. Guerios SD, Wang ZY, Bjorling DE. Nerve growth factor mediates peripheral mechanical hypersensitivity that accompanies experimental cystitis in mice. Neurosci Lett. 2006;392:193–7.

    Article  CAS  PubMed  Google Scholar 

  65. Kanai A, Andersson KE. Bladder afferent signaling: recent findings. J Urol. 2010;183:1288–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, et al. International union of pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev. 2002;54:161–202.

    Article  CAS  PubMed  Google Scholar 

  67. Kavia RB, De Ridder D, Constantinescu CS, Stott CG, Fowler CJ. Randomized controlled trial of sativex to treat detrusor overactivity in multiple sclerosis. Mult Scler. 2010;16:1349–59.

    Article  CAS  PubMed  Google Scholar 

  68. Wade DT, Robson P, House H, Makela P, Aram J. A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms, Clin Rehabil. 2003;17(1):21–9.

  69. Wade DT, Makela P, Robson P, House H, Bateman C. Do cannabis-based medicinal extracts have general or specific effects on symptoms in multiple sclerosis? A double-blind, randomized, placebo-controlled study on 160 patients, Mult Scler. 2004;10(4):434–41.

  70. Martyn CN, Illis LS, Thom J. Nabilone in the treatment of multiple sclerosis, Lancet, 1995;345(8949):579.

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Authors and Affiliations

  1. NHS Foundation Trust, Kettering General Hospital, Rothwell Road, Kettering, Northants, NN16 8UZ, UK

    Evangelia Bakali

  2. Department of Health Sciences, College of Medicine, University of Leicester, Maurice Shock Building, University Road, Leicester, LE1 7RH, UK

    Douglas Tincello

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  1. Evangelia Bakali
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Correspondence to Evangelia Bakali.

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Bakali, E., Tincello, D. Current Understanding of Cannabinoids and Detrusor Overactivity. Curr Bladder Dysfunct Rep 12, 86–94 (2017). https://doi.org/10.1007/s11884-017-0414-7

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