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The endocannabinoid system — a target for the treatment of LUTS?

Key Points

  • Endogenously produced cannabinoids (termed 'endocannabinoids') can modify the micturition process in animal models

  • Activation of cannabinoid receptors by endocannabinoids reduces the firing of bladder sensory nerves and decreases micturition frequency in rodent models of inflammatory bladder hyperalgesia

  • Based on data from these models, the endocannabinoid system might influence sensory dysfunction during bladder pathologies

  • Local endocannabinoid and/or fatty-acid ethanolamide signals are recruited in models of bladder inflammation

  • Data obtained from rats with bladder overactivity or from patients with detrusor overactivity and/or bladder pain implicate neuronal cannabinoid receptor 1 plasticity in the pathophysiology of chronic bladder dysfunctions

  • Blockade of endocannabinoid degradation and fatty-acid ethanolamides by fatty-acid amide hydrolase inhibitors has been shown to ameliorate bladder disorders in various experimental models, but no information is currently available regarding humans

Abstract

Lower urinary tract symptoms (LUTS) are common in all age groups and both sexes, resulting in tremendous personal suffering and a substantial burden to society. Antimuscarinic drugs are the mainstay of symptom management in patients with LUTS, although their clinical utility is limited by the high prevalence of adverse effects, which often limit patients' long-term adherence to these agents. Data from controversial studies in the 1990s revealed the positive effects of marijuana-based compounds on LUTS, and sparked an interest in the possibility of treating bladder disorders with cannabis. Increased understanding of cannabinoid receptor pharmacology and the discovery of endogenous ligands of these receptors has prompted debate and further research into the clinical utility of exogenous cannabinoid receptor agonists relative to the unwanted psychotropic effects of these agents. Currently, the endocannabinoid system is considered as a potential drug target for pharmacological management of LUTS, with a more favourable adverse event profile than antimuscarinic agents.

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Figure 1: Functional organization of the endocannabinoid system during normal micturition.
Figure 2: Functional organization of the endocannabinoid system during bladder dysfunction.
Figure 3: Functional organization of CB1 expression in experimental models of bladder overactivity.

References

  1. Abrams, P. et al. Fourth International Consultation on Incontinence Recommendations of the International Scientific Committee: evaluation and treatment of urinary incontinence, pelvic organ prolapse, and fecal incontinence. Neurourol. Urodyn. 29, 213–240 (2010).

    CAS  PubMed  Article  Google Scholar 

  2. Milsom, I. et al. Global prevalence and economic burden of urgency urinary incontinence: a systematic review. Eur. Urol. 65, 79–95 (2014).

    PubMed  Article  Google Scholar 

  3. Thuroff, J. W. et al. EAU guidelines on urinary incontinence. Eur. Urol. 59, 387–400 (2011).

    PubMed  Article  Google Scholar 

  4. Gormley, E. A. et al. Diagnosis and treatment of overactive bladder (non-neurogenic) in adults: AUA/SUFU guideline. J. Urol. 188, 2455–2463 (2012).

    PubMed  Article  Google Scholar 

  5. Oelke, M. et al. EAU guidelines on the treatment and follow-up of non-neurogenic male lower urinary tract symptoms including benign prostatic obstruction. Eur. Urol. 64, 118–140 (2013).

    PubMed  Article  Google Scholar 

  6. McVary, K. T. et al. Update on AUA guideline on the management of benign prostatic hyperplasia. J. Urol. 185, 1793–1803 (2011).

    PubMed  Article  Google Scholar 

  7. Sexton, C. C. et al. Persistence and adherence in the treatment of overactive bladder syndrome with anticholinergic therapy: a systematic review of the literature. Int. J. Clin. Pract. 65, 567–585 (2011).

    CAS  PubMed  Article  Google Scholar 

  8. Andersson, K. E., Campeau, L. & Olshansky, B. Cardiac effects of muscarinic receptor antagonists used for voiding dysfunction. Br. J. Clin. Pharmacol. 72, 186–196 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. Consroe, P., Musty, R., Rein, J., Tillery, W. & Pertwee, R. The perceived effects of smoked cannabis on patients with multiple sclerosis. Eur. Neurol. 38, 44–48 (1997).

    CAS  PubMed  Article  Google Scholar 

  10. Brady, C. M. et al. An open-label pilot study of cannabis-based extracts for bladder dysfunction in advanced multiple sclerosis. Mult. Scler. 10, 425–433 (2004).

    CAS  PubMed  Article  Google Scholar 

  11. Freeman, R. M. et al. The effect of cannabis on urge incontinence in patients with multiple sclerosis: a multicentre, randomised placebo-controlled trial (CAMS-LUTS). Int. Urogynecol. J. Pelv. Floor Dysfunct. 17, 636–641 (2006).

    CAS  Article  Google Scholar 

  12. Kavia, R. B., De Ridder, D., Constantinescu, C. S., Stott, C. G. & Fowler, C. J. Randomized controlled trial of Sativex to treat detrusor overactivity in multiple sclerosis. Mult. Scler. 16, 1349–1359 (2010).

    CAS  PubMed  Article  Google Scholar 

  13. Koppel, B. S. et al. Systematic review: efficacy and safety of medical marijuana in selected neurologic disorders: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology 82, 1556–1563 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  14. van den Elsen, G. A. et al. Efficacy and safety of medical cannabinoids in older subjects: a systematic review. Ageing Res. Rev. 14, 56–64 (2014).

    CAS  PubMed  Article  Google Scholar 

  15. Di Marzo, V. Targeting the endocannabinoid system: to enhance or reduce? Nat. Rev. Drug Discov. 7, 438–455 (2008).

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  17. Blankman, J. L. & Cravatt, B. F. Chemical probes of endocannabinoid metabolism. Pharmacol. Rev. 65, 849–871 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  18. Pertwee, R. G. Elevating endocannabinoid levels: pharmacological strategies and potential therapeutic applications. Proc. Nutr. Soc. 73, 96–105 (2014).

    CAS  PubMed  Article  Google Scholar 

  19. Gratzke, C. et al. Distribution and function of cannabinoid receptors 1 and 2 in the rat, monkey and human bladder. J. Urol. 181, 1939–1948 (2009).

    CAS  PubMed  Article  Google Scholar 

  20. Ong, W. Y. & Mackie, K. A light and electron microscopic study of the CB1 cannabinoid receptor in the primate spinal cord. J. Neurocytol. 28, 39–45 (1999).

    CAS  PubMed  Article  Google Scholar 

  21. Farquhar-Smith, W. P. et al. Cannabinoid CB1 receptor expression in rat spinal cord. Mol. Cell. Neurosci. 15, 510–521 (2000).

    CAS  PubMed  Article  Google Scholar 

  22. Merriam, F. V., Wang, Z. Y., Guerios, S. D. & Bjorling, D. E. Cannabinoid receptor 2 is increased in acutely and chronically inflamed bladder of rats. Neurosci. Lett. 445, 130–134 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. Veress, G. et al. Characterisation of cannabinoid 1 receptor expression in the perikarya, and peripheral and spinal processes of primary sensory neurons. Brain Struct. Funct. 218, 733–750 (2013).

    CAS  PubMed  Article  Google Scholar 

  24. Füllhase, C. et al. Spinal neuronal cannabinoid receptors mediate urodynamic effects of systemic fatty acid amide hydrolase (FAAH) inhibition in rats. Neurourol. Urodyn. 35, 464–470 (2016).

    PubMed  Article  CAS  Google Scholar 

  25. Aizawa, N. et al. Inhibition of peripheral FAAH depresses activities of bladder mechanosensitive nerve fibers of the rat. J. Urol. 192, 956–963 (2014).

    CAS  PubMed  Article  Google Scholar 

  26. Svizenska, I., Dubovy, P. & Sulcova, A. Cannabinoid receptors 1 and 2 (CB1 and CB2), their distribution, ligands and functional involvement in nervous system structures — a short review. Pharmacol. Biochem. Behav. 90, 501–511 (2008).

    CAS  PubMed  Article  Google Scholar 

  27. Pertwee, R. G. et al. International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB1 and CB2 . Pharmacol. Rev. 62, 588–631 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. Bakali, E. et al. Distribution and function of the endocannabinoid system in the rat and human bladder. Int. Urogynecol. J. 24, 855–863 (2013).

    PubMed  Article  Google Scholar 

  29. Fezza, F. et al. Endocannabinoids, related compounds and their metabolic routes. Molecules 19, 17078–17106 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  30. Dinis, P. 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. 24, 11253–11263 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. Merriam, F. V., Wang, Z. Y., Hillard, C. J., Stuhr, K. L. & Bjorling, D. E. Inhibition of fatty acid amide hydrolase suppresses referred hyperalgesia induced by bladder inflammation. BJU Int. 108, 1145–1149 (2011).

    CAS  PubMed  Article  Google Scholar 

  32. Pessina, F. et al. Protective effect of palmitoylethanolamide in a rat model of cystitis. J. Urol. 193, 1401–1408 (2015).

    CAS  PubMed  Article  Google Scholar 

  33. Schreiber, A. et al. Expression of monoacylglycerase (MAGL) in the human lower urinary tract: a new target for intervention into the endocannabinoid system? Eur. Urol. http://dx.doi.org/10.1016/S1569-9056(14)60364-X (2014).

  34. Aizawa, N. 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 fibers in rats. BJU Int. http://dx.doi.org/10.1111/bju.13223 (2013).

  35. Fullhase, C. et al. Spinal cord FAAH in normal micturition control and bladder overactivity in awake rats. J. Urol. 189, 2364–2370 (2013).

    PubMed  Article  CAS  Google Scholar 

  36. Wei, B. Q., Mikkelsen, T. S., McKinney, M. K., Lander, E. S. & Cravatt, B. F. A second fatty acid amide hydrolase with variable distribution among placental mammals. J. Biol. Chem. 281, 36569–36578 (2006).

    CAS  PubMed  Article  Google Scholar 

  37. Benigni, F. & Hedlund, P. Reply from Authors re: apostolos apostolidis. taming the cannabinoids: new potential in the pharmacologic control of lower urinary tract dysfunction. Eur. Urol. 61, 107–111 (2012).

    Article  Google Scholar 

  38. Huestis, M. A. Human cannabinoid pharmacokinetics. Chem. Biodivers. 4, 1770–1804 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. Chopda, G. R. et al. Diuretic effects of cannabinoid agonists in mice. Eur. J. Pharmacol. 721, 64–69 (2013).

    CAS  PubMed  Article  Google Scholar 

  40. Paronis, C. A. et al. Diuretic effects of cannabinoids. J. Pharmacol. Exp. Ther. 344, 8–14 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. Murataeva, N., Mackie, K. & Straiker, A. The CB2-preferring agonist JWH015 also potently and efficaciously activates CB1 in autaptic hippocampal neurons. Pharmacol. Res. 66, 437–442 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  42. Dhopeshwarkar, A. & Mackie, K. CB2 cannabinoid receptors as a therapeutic target-what does the future hold? Mol. Pharmacol. 86, 430–437 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  43. Pertwee, R. G. & Fernando, S. R. Evidence for the presence of cannabinoid CB1 receptors in mouse urinary bladder. Br. J. Pharmacol. 118, 2053–2058 (1996).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. Tyagi, V. et al. Differential expression of functional cannabinoid receptors in human bladder detrusor and urothelium. J. Urol. 181, 1932–1938 (2009).

    CAS  PubMed  Article  Google Scholar 

  45. Gratzke, C. et al. Effects of cannabinor, a novel selective cannabinoid 2 receptor agonist, on bladder function in normal rats. Eur. Urol. 57, 1093–1100 (2010).

    CAS  PubMed  Article  Google Scholar 

  46. Capasso, R. et al. Inhibitory effect of standardized cannabis sativa extract and its ingredient cannabidiol on rat and human bladder contractility. Urology 77, 1006.e9–1006.e15 (2011).

    Article  Google Scholar 

  47. Di Marzo, V. & De Petrocellis, L. Why do cannabinoid receptors have more than one endogenous ligand? Phil. Trans. R. Soc. B 367, 3216–3228 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  48. Capasso, R. et al. Palmitoylethanolamide normalizes intestinal motility in a model of post-inflammatory accelerated transit: involvement of CB1 receptors and TRPV1 channels. Br. J. Pharmacol. 171, 4026–4037 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. Martin, R. S. et al. 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 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  50. Fullhase, C. et al. Bladder function in a cannabinoid receptor type 1 knockout mouse. BJU Int. 113, 144–151 (2014).

    PubMed  Article  CAS  Google Scholar 

  51. Li, Y. et al. Cannabinoid receptors 1 and 2 are associated with bladder dysfunction in an experimental diabetic rat model. BJU Int. 112, E143–E150 (2013).

    CAS  PubMed  Article  Google Scholar 

  52. Hayn, M. H. et al. Functional and immunohistochemical characterization of CB1 and CB2 receptors in rat bladder. Urology 72, 1174–1178 (2008).

    PubMed  Article  Google Scholar 

  53. Walczak, J. S., Price, T. J. & Cervero, F. Cannabinoid CB1 receptors are expressed in the mouse urinary bladder and their activation modulates afferent bladder activity. Neuroscience 159, 1154–1163 (2009).

    CAS  PubMed  Article  Google Scholar 

  54. Gandaglia, G. et al. The fatty acid amide hydrolase inhibitor oleoyl ethyl amide counteracts bladder overactivity in female rats. Neurourol. Urodyn. 33, 1251–1258 (2014).

    CAS  PubMed  Article  Google Scholar 

  55. Strittmatter, 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. 61, 98–106 (2012).

    CAS  PubMed  Article  Google Scholar 

  56. Campeau, L. et al. Characterization of bladder function in a cannabinoid receptor type 2 knockout mouse in vivo and in vitro. Neurourol. Urodyn. 33, 566–570 (2014).

    CAS  PubMed  Article  Google Scholar 

  57. Hiragata, S. et al. Effects of IP-751, ajulemic acid, on bladder overactivity induced by bladder irritation in rats. Urology 70, 202–208 (2007).

    PubMed  Article  Google Scholar 

  58. Rinaldi-Carmona, M. et al. Modulation of CB1 cannabinoid receptor functions after a long-term exposure to agonist or inverse agonist in the Chinese hamster ovary cell expression system. J. Pharmacol. Exp. Ther. 287, 1038–1047 (1988).

    Google Scholar 

  59. Wang, Z. Y., Wang, P. & Bjorling, D. E. Activation of cannabinoid receptor 1 inhibits increased bladder activity induced by nerve growth factor. Neurosci. Lett. 589, 19–24 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. Wang, Z. Y., Wang, P., Hillard, C. J. & Bjorling, D. E. Attenuation of cystitis and pain sensation in mice lacking fatty acid amide hydrolase. J. Mol. Neurosci. 55, 968–976 (2015).

    CAS  PubMed  Article  Google Scholar 

  61. Davis, J., Maillet, M., Miano, J. M. & Molkentin, J. D. Lost in transgenesis: a user's guide for genetically manipulating the mouse in cardiac research. Circ. Res. 111, 761–777 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  63. Clapper, J. R. et al. Anandamide suppresses pain initiation through a peripheral endocannabinoid mechanism. Nat. Neurosci. 13, 1265–1270 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  64. Yaksh, T. L. & Rudy, T. A. Chronic catheterization of the spinal subarachnoid space. Physiol. Behav. 17, 1031–1036 (1976).

    CAS  PubMed  Article  Google Scholar 

  65. Farquhar-Smith, W. P., Jaggar, S. I. & Rice, A. S. Attenuation of nerve growth factor-induced visceral hyperalgesia via cannabinoid CB1 and CB2-like receptors. Pain 97, 11–21 (2002).

    CAS  PubMed  Article  Google Scholar 

  66. Farquhar-Smith, W. P. & Rice, A. S. Administration of endocannabinoids prevents a referred hyperalgesia associated with inflammation of the urinary bladder. Anesthesiology 94, 507–513; discussion; 6A (2001).

    CAS  PubMed  Article  Google Scholar 

  67. Guan, Y., Zhang, Y., Davis, L. & Breyer, M. D. Expression of peroxisome proliferator-activated receptors in urinary tract of rabbits and humans. Am. J. Physiol. 273, F1013–F1022 (1997).

    CAS  PubMed  Google Scholar 

  68. Khasabova, I. A., Xiong, Y., Coicou, L. G., Piomelli, D. & Seybold, V. Peroxisome proliferator-activated receptor alpha mediates acute effects of palmitoylethanolamide on sensory neurons. J. Neurosci. 32, 12735–12743 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. Moreno-Santos, I. et al. Computational and biological evaluation of N-octadecyl-N′-propylsulfamide, a selective PPARα agonist structurally related to N-acylethanolamines. PLoS ONE 9, e92195 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  70. Tambaro, S., Casu, M. A., Mastinu, A. & Lazzari, P. Evaluation of selective cannabinoid CB1 and CB2 receptor agonists in a mouse model of lipopolysaccharide-induced interstitial cystitis. Eur. J. Pharmacol. 729, 67–74 (2014).

    CAS  PubMed  Article  Google Scholar 

  71. Miller, L. K. & Devi, L. A. The highs and lows of cannabinoid receptor expression in disease: mechanisms and their therapeutic implications. Pharmacol. Rev. 63, 461–470 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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

    Article  Google Scholar 

  73. Bakali, E., McDonald, J., Elliott, R. A., Lambert, D. G. & Tincello, D. G. Cannabinoid receptor expression in the bladder is altered in detrusor overactivity. Int. Urogynecol. J. 27, 129–139 (2016).

    PubMed  Article  Google Scholar 

  74. Huggins, J. P., Smart, T. S., Langman, S., Taylor, L. & Young, T. An efficient randomised, placebo-controlled clinical trial with the irreversible fatty acid amide hydrolase-1 inhibitor PF-04457845, which modulates endocannabinoids but fails to induce effective analgesia in patients with pain due to osteoarthritis of the knee. Pain 153, 1837–1846 (2012).

    CAS  PubMed  Article  Google Scholar 

  75. Maione, S., Costa, B. & Di Marzo, V. Endocannabinoids: a unique opportunity to develop multitarget analgesics. Pain 154, S87–S93 (2013).

    CAS  PubMed  Article  Google Scholar 

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Hedlund, P., Gratzke, C. The endocannabinoid system — a target for the treatment of LUTS?. Nat Rev Urol 13, 463–470 (2016). https://doi.org/10.1038/nrurol.2016.110

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