New Modulatory Pathways in Micturition Reflex Function THERE is still much to learn concerning the basic science underlying micturition reflex pathways, modulation of bladder function and plasticity in these neural circuits following neural injury, disease or inflammation. In this issue of The Journal Aizawa et al (page 956) highlight this topic.1 The role of cannabinoids and the endocannabinoid system in lower urinary tract (LUT) function and dysfunction has been the focus of study for more than a decade with many laboratories focusing on components of the endocannabinoid system, including cannabinoid (CB) receptors (CB1 and CB2), their endogenous ligands and related enzymes that balance the biosynthesis and degradation of endocannabinoids and related fatty acid amides (FAAs).2,3 A key protein in the degradation of anandamide and FAAs is the enzyme FAA hydrolase (FAAH).4,5 Complex neural circuitry underlies the micturition reflex. Perhaps because of this complexity, micturition reflex function is often compromised as a result of diverse neural injuries, diseases and disorders, including spinal cord injury, stroke, multiple sclerosis (MS) and Parkinson disease.6,7 Although the etiology is unclear, functional disorders of the bladder, including bladder pain syndrome/interstitial cystitis and overactive bladder, also exhibit bladder dysfunction (ie increased voiding frequency) with and without pelvic pain, respectively. Given the diversity of neural injuries and disease, identifying novel, modulatory pathways of micturition reflex function in health and disease is necessary not only to understand basic science underlying micturition but also to develop pharmacological treatments. Although a number of LUT targets have gained attention, there is continued and growing interest in the endocannabinoid system as a key modulatory pathway of LUT function in health and dysfunction.2,3 Storage and periodic elimination of urine is organized in the central and peripheral nervous system to coordinate the activities of the bladder and urethra. The micturition reflex is organized as a simple on-off system, switching between 2 modes of operation in the bladder: storage and elimination.6,8
0022-5347/14/1923-0638/0 THE JOURNAL OF UROLOGY® © 2014 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
638
j
www.jurology.com
AND
RESEARCH, INC.
During the storage phase somatic and sympathetic excitatory inputs to the urethral sphincters and sympathetic inhibitory inputs to the bladder wall are tonically active while parasympathetic pathways are inactive.6,8 During reflexive or voluntary micturition parasympathetic input to the bladder wall is excited and somatosympathetic input to the bladder wall and urethral sphincters is inhibited.6,8 Unlike local spinal reflexes that underlie most of the storage phase the reflex mechanisms that underlie elimination are predominately influenced by supraspinal modulation in the pontine micturition center.6,8 The switch from the storage to the elimination phase is elicited by slowly adapting mechanoreceptors in the bladder wall.7 As hydrostatic pressure increases, bladder afferent (thinly myelinated Ad) fibers convey information via the hypogastric and pelvic nerves.6,8 Bladder afferent nerves that terminate peripherally throughout the tunica mucosa and tunica muscularis propria also include unmyelinated C-fibers, which are responsive to nociceptive activation by chemicals (eg capsaicin and menthol), extreme intravesical pressure and inflammation.6 Under normal conditions the C-fiber bladder afferent population is typically quiescent during bladder filling but C-fiber activation may contribute to the development of LUT symptoms and pathological conditions of the bladder.8 A large body of compelling studies supports roles for components of the endocannabinoid system in the modulation of bladder function.2,3 Bladder symptom specific effects of cannabinoids can be first traced to several MS studies and a recent systematic review addressed the effectiveness of cannabinoids for bladder dysfunction in patients with MS.9 Reported improvements in LUT symptoms in patients with MS have stimulated tremendous interest in understanding the effects of the endocannabinoid system in LUT function and the underlying mechanisms of action. Not surprising side effects, including dizziness, attention deficit, fatigue and disorientation, were noted and correlated with duration of use. The expression and distribution of CB1 and CB2 receptors were demonstrated in LUT
http://dx.doi.org/10.1016/j.juro.2014.06.034 Vol. 192, 638-639, September 2014 Printed in U.S.A.
NEW MODULATORY PATHWAYS IN MICTURITION REFLEX FUNCTION
tissues involved in micturition reflexes (eg bladder nerves, urothelium, detrusor, dorsal root ganglia and spinal cord) in diverse species, including humans. CB1 and CB2 receptors, and FAAH are expressed in nerves that co-express sensory markers, including P2X3, TRPV1, TRPV4 and CGRP.3 Inhibitory effects by cannabinoids on nerve mediated bladder contractions and bladder afferent nerve activity have been demonstrated but there is lack of consensus on the involvement of specific CB receptor subtypes.2,3 Systemic and intravesical administration of cannabinoids in animal models of LUT in health or disease are consistent with inhibitory effects on afferent pathways underlying micturition.3 In addition, numerous studies have shown cannabinoid induced reductions in nociceptive transmission involving CB1 and CB2 receptors. Alternative approaches that involve the endocannabinoid system in LUT function focus on drugs that target peripheral CB receptors and/or affect the turnover of endocannabinoids or FAA. The strategy behind FAAH inhibitors is to amplify endocannabinoid activity and also minimize central nervous system related side effects of cannabinoids. FAAH is distributed in urothelium and lumbosacral dorsal root ganglia, where it is co-expressed with the sensory neuron markers TRPV1 and CGRP.3 FAAH inhibitors alter sensory urodynamic parameters (eg increased intermicturition interval, increased
639
bladder capacity and increased voided volumes) and reduce the firing of bladder afferents (Ad and Cfiber) via CB1 and CB2 dependent mechanisms.10,11 Aizawa et al expand our knowledge of the use of FAAH inhibitors to modulate LUT function.1 Using the peripherally active FAAH inhibitor URB937 they noted a reduction in bladder distention induced activity of Ad and C-fiber bladder afferents in vivo that was mediated by CB1 and CB2 receptors. In the future additional studies are needed to address 1) the mechanisms underlying the FAAH inhibitor mediated reductions in bladder afferent nerve activity and whether there are mechanisms specific to Ad and C-fibers, 2) FAAH inhibitor effects on urodynamic parameters in preclinical animal models of LUT dysfunction and 3) FAAH inhibitor effects on nociceptive outcomes in animal models of LUT dysfunction and pelvic pain. These future studies will help us determine the potential broad impact of modulating the cannabinoids and the endocannabinoid system in LUT function. Margaret A. Vizzard Department of Neurological Sciences University of Vermont College of Medicine Burlington, Vermont Financial interest and/or other relationship with National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health.
REFERENCES 1. Aizawa N, Hedlund P, F€ullhase C et al: Inhibition of peripheral FAAH depresses activities of bladder mechanosensitive nerve fibers of the rat. J Urol 2014; 192: 956. 2. Ruggieri MR Sr: Cannabinoids: potential targets for bladder dysfunction. Handb Exp Pharmacol 2011; 202: 425. 3. Hedlund P: Cannabinoids and the endocannabinoid system in lower urinary tract function and dysfunction. Neurourol Urodyn 2014; 33: 46. 4. Merriam FV, Wang ZY, Hillard CJ et al: Inhibition of fatty acid amide hydrolase suppresses referred hyperalgesia induced by bladder inflammation. BJU Int 2011; 108: 1145.
5. Gandaglia G, Strittmatter F, La Croce G et al: The fatty acid amide hydrolase inhibitor oleoyl ethyl amide counteracts bladder overactivity in female rats. Neurourol Urodyn 2013; Epub ahead of print. 6. Fowler CJ, Griffiths D and de Groat WC: The neural control of micturition. Nat Rev Neurosci 2008; 9: 453. 7. Andersson KE: Mechanisms of disease: central nervous system involvement in overactive bladder syndrome. Nat Clin Pract Urol 2004; 1: 103. 8. de Groat WC and Wickens C: Organization of the neural switching circuitry underlying reflex micturition. Acta Physiol (Oxf) 2013; 207: 66.
9. Koppel BS, Brust JC, Fife T 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 2014; 82: 1556. 10. F€ullhase C, Russo A, Castiglione F et al: Spinal cord FAAH in normal micturition control and bladder overactivity in awake rats. J Urol 2013; 189: 2364. 11. Moreno-Sanz G, Barrera B, Guijarro A et al: The ABC membrane transporter ABCG2 prevents access of FAAH inhibitor URB937 to the central nervous system. Pharmacol Res 2011; 64: 359.
0022-5347/14/1923-0638/0 THE JOURNAL OF UROLOGY® © 2014 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
638
j
www.jurology.com
AND
RESEARCH, INC.
During the storage phase somatic and sympathetic excitatory inputs to the urethral sphincters and sympathetic inhibitory inputs to the bladder wall are tonically active while parasympathetic pathways are inactive.6,8 During reflexive or voluntary micturition parasympathetic input to the bladder wall is excited and somatosympathetic input to the bladder wall and urethral sphincters is inhibited.6,8 Unlike local spinal reflexes that underlie most of the storage phase the reflex mechanisms that underlie elimination are predominately influenced by supraspinal modulation in the pontine micturition center.6,8 The switch from the storage to the elimination phase is elicited by slowly adapting mechanoreceptors in the bladder wall.7 As hydrostatic pressure increases, bladder afferent (thinly myelinated Ad) fibers convey information via the hypogastric and pelvic nerves.6,8 Bladder afferent nerves that terminate peripherally throughout the tunica mucosa and tunica muscularis propria also include unmyelinated C-fibers, which are responsive to nociceptive activation by chemicals (eg capsaicin and menthol), extreme intravesical pressure and inflammation.6 Under normal conditions the C-fiber bladder afferent population is typically quiescent during bladder filling but C-fiber activation may contribute to the development of LUT symptoms and pathological conditions of the bladder.8 A large body of compelling studies supports roles for components of the endocannabinoid system in the modulation of bladder function.2,3 Bladder symptom specific effects of cannabinoids can be first traced to several MS studies and a recent systematic review addressed the effectiveness of cannabinoids for bladder dysfunction in patients with MS.9 Reported improvements in LUT symptoms in patients with MS have stimulated tremendous interest in understanding the effects of the endocannabinoid system in LUT function and the underlying mechanisms of action. Not surprising side effects, including dizziness, attention deficit, fatigue and disorientation, were noted and correlated with duration of use. The expression and distribution of CB1 and CB2 receptors were demonstrated in LUT
http://dx.doi.org/10.1016/j.juro.2014.06.034 Vol. 192, 638-639, September 2014 Printed in U.S.A.
NEW MODULATORY PATHWAYS IN MICTURITION REFLEX FUNCTION
tissues involved in micturition reflexes (eg bladder nerves, urothelium, detrusor, dorsal root ganglia and spinal cord) in diverse species, including humans. CB1 and CB2 receptors, and FAAH are expressed in nerves that co-express sensory markers, including P2X3, TRPV1, TRPV4 and CGRP.3 Inhibitory effects by cannabinoids on nerve mediated bladder contractions and bladder afferent nerve activity have been demonstrated but there is lack of consensus on the involvement of specific CB receptor subtypes.2,3 Systemic and intravesical administration of cannabinoids in animal models of LUT in health or disease are consistent with inhibitory effects on afferent pathways underlying micturition.3 In addition, numerous studies have shown cannabinoid induced reductions in nociceptive transmission involving CB1 and CB2 receptors. Alternative approaches that involve the endocannabinoid system in LUT function focus on drugs that target peripheral CB receptors and/or affect the turnover of endocannabinoids or FAA. The strategy behind FAAH inhibitors is to amplify endocannabinoid activity and also minimize central nervous system related side effects of cannabinoids. FAAH is distributed in urothelium and lumbosacral dorsal root ganglia, where it is co-expressed with the sensory neuron markers TRPV1 and CGRP.3 FAAH inhibitors alter sensory urodynamic parameters (eg increased intermicturition interval, increased
639
bladder capacity and increased voided volumes) and reduce the firing of bladder afferents (Ad and Cfiber) via CB1 and CB2 dependent mechanisms.10,11 Aizawa et al expand our knowledge of the use of FAAH inhibitors to modulate LUT function.1 Using the peripherally active FAAH inhibitor URB937 they noted a reduction in bladder distention induced activity of Ad and C-fiber bladder afferents in vivo that was mediated by CB1 and CB2 receptors. In the future additional studies are needed to address 1) the mechanisms underlying the FAAH inhibitor mediated reductions in bladder afferent nerve activity and whether there are mechanisms specific to Ad and C-fibers, 2) FAAH inhibitor effects on urodynamic parameters in preclinical animal models of LUT dysfunction and 3) FAAH inhibitor effects on nociceptive outcomes in animal models of LUT dysfunction and pelvic pain. These future studies will help us determine the potential broad impact of modulating the cannabinoids and the endocannabinoid system in LUT function. Margaret A. Vizzard Department of Neurological Sciences University of Vermont College of Medicine Burlington, Vermont Financial interest and/or other relationship with National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health.
REFERENCES 1. Aizawa N, Hedlund P, F€ullhase C et al: Inhibition of peripheral FAAH depresses activities of bladder mechanosensitive nerve fibers of the rat. J Urol 2014; 192: 956. 2. Ruggieri MR Sr: Cannabinoids: potential targets for bladder dysfunction. Handb Exp Pharmacol 2011; 202: 425. 3. Hedlund P: Cannabinoids and the endocannabinoid system in lower urinary tract function and dysfunction. Neurourol Urodyn 2014; 33: 46. 4. Merriam FV, Wang ZY, Hillard CJ et al: Inhibition of fatty acid amide hydrolase suppresses referred hyperalgesia induced by bladder inflammation. BJU Int 2011; 108: 1145.
5. Gandaglia G, Strittmatter F, La Croce G et al: The fatty acid amide hydrolase inhibitor oleoyl ethyl amide counteracts bladder overactivity in female rats. Neurourol Urodyn 2013; Epub ahead of print. 6. Fowler CJ, Griffiths D and de Groat WC: The neural control of micturition. Nat Rev Neurosci 2008; 9: 453. 7. Andersson KE: Mechanisms of disease: central nervous system involvement in overactive bladder syndrome. Nat Clin Pract Urol 2004; 1: 103. 8. de Groat WC and Wickens C: Organization of the neural switching circuitry underlying reflex micturition. Acta Physiol (Oxf) 2013; 207: 66.
9. Koppel BS, Brust JC, Fife T 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 2014; 82: 1556. 10. F€ullhase C, Russo A, Castiglione F et al: Spinal cord FAAH in normal micturition control and bladder overactivity in awake rats. J Urol 2013; 189: 2364. 11. Moreno-Sanz G, Barrera B, Guijarro A et al: The ABC membrane transporter ABCG2 prevents access of FAAH inhibitor URB937 to the central nervous system. Pharmacol Res 2011; 64: 359.
