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Bonanni R, Ratano P, Cariati I, Tancredi V, Cifelli P. Treatment Strategies for Painful Pelvic Floor Conditions: A Focus on the Potential Benefits of Cannabidiol. Biomolecules 2024; 14:1627. [PMID: 39766334 PMCID: PMC11727302 DOI: 10.3390/biom14121627] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2024] [Revised: 12/17/2024] [Accepted: 12/18/2024] [Indexed: 01/15/2025] Open
Abstract
Painful conditions of the pelvic floor include a set of disorders of the pelvic region, discreetly prevalent in the female population, in which pain emerges as the predominant symptom. Such disorders have a significant impact on quality of life as they impair couple relationships and promote states of anxiety and irascibility in affected individuals. Although numerous treatment approaches have been proposed for the management of such disorders, there is a need to identify strategies to promote muscle relaxation, counter pelvic pain, and reduce inflammation. The endocannabinoid system (ECS) represents a complex system spread throughout the body and is involved in the regulation of numerous physiological processes representing a potential therapeutic target for mood and anxiety disorders as well as pain management. Cannabidiol (CBD), acting on the ECS, can promote relief from hyperalgesia and allodynia typical of disorders affecting the pelvic floor and promote muscle relaxation by restoring balance to this delicate anatomical region. However, its use is currently limited due to a lack of evidence supporting its efficacy and harmlessness, and the mechanism of action on the ECS remains partially unexplored to this day. This comprehensive review of the literature examines the impact of pain disorders affecting the pelvic floor and major treatment approaches and brings together the main evidence supporting CBD in the management of such disorders.
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Affiliation(s)
- Roberto Bonanni
- Department of Biomedicine and Prevention, “Tor Vergata” University of Rome, Via Montpellier 1, 00133 Rome, Italy;
| | - Patrizia Ratano
- Department of Food Safety, Nutrition and Veterinary Public Health, Istituto Superiore di Sanità (ISS), 00161 Rome, Italy;
| | - Ida Cariati
- Department of Systems Medicine, “Tor Vergata” University of Rome, Via Montpellier 1, 00133 Rome, Italy;
| | - Virginia Tancredi
- Department of Systems Medicine, “Tor Vergata” University of Rome, Via Montpellier 1, 00133 Rome, Italy;
- Centre of Space Bio-Medicine, “Tor Vergata” University of Rome, Via Montpellier 1, 00133 Rome, Italy
| | - Pierangelo Cifelli
- Department of Applied Clinical and Biotechnological Sciences, University of L’Aquila, 67100 L’Aquila, Italy;
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Cho KJ, Hashimoto M, Karnup S, Matsuoka K, Kamijo T, Kim JC, Koh JS, Yoshimura N. Improvement of lower urinary tract dysfunction by a monoacylglycerol lipase inhibitor in mice with spinal cord injury. Neurourol Urodyn 2024; 43:1207-1216. [PMID: 38533637 PMCID: PMC11153015 DOI: 10.1002/nau.25458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2024] [Revised: 03/06/2024] [Accepted: 03/15/2024] [Indexed: 03/28/2024]
Abstract
AIMS Activation of the endocannabinoid system by monoacylglycerol lipase (MAGL) blockade may affect the lower urinary tract function. We investigated the effect of an MAGL inhibitor, MJN110, on neurogenic lower urinary tract dysfunction (LUTD) in the mouse model of spinal cord injury (SCI). METHODS Female C57BL/6 mice that underwent spinal cord transection at T8-10 level were divided into three groups consisting of (1) vehicle-treated SCI mice, (2) 5 mg/kg, or (3) 10 mg/kg of MJN110-treated SCI mice. MJN110 and vehicle were administered intraperitoneally for 7 days from 4 weeks after spinal cord transection. We then conducted awake cystometrograms and compared urodynamic parameters between three groups. The expression of cannabinoid (CB) receptors, TRP receptors, and inflammatory cytokines in L6-S1 dorsal root ganglia (DRG) or the bladder mucosa were evaluated and compared among three groups. Changes in the level of serum 2-arachidonoylglycerol (2-AG) and bladder MAGL were also evaluated. RESULTS In the cystometrogram, detrusor overactivity (DO) parameters, such as the number of nonvoiding contraction (NVC), a ratio of time to the 1st NVC to intercontraction interval (ICI), and NVC integrals were improved by MJN110 treatment, and some effects were dose dependent. Although MJN110 did not improve voiding efficiency, it decreased bladder capacity, ICI, and residual urine volume compared to vehicle injection. MJN110 treatment groups had lower CB2, TRPV1, TRPA1, and inflammatory cytokines mRNA levels in DRG and bladder mucosa. Serum 2-AG was increased, and bladder MAGL was decreased after MAGL inhibitor treatment. CONCLUSIONS MAGL inhibition improved LUTD including attenuation of DO after SCI. Thus, MAGL can be a therapeutic target for neurogenic LUTD after SCI.
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MESH Headings
- Animals
- Monoacylglycerol Lipases/antagonists & inhibitors
- Monoacylglycerol Lipases/metabolism
- Spinal Cord Injuries/physiopathology
- Spinal Cord Injuries/drug therapy
- Spinal Cord Injuries/complications
- Spinal Cord Injuries/metabolism
- Female
- Mice, Inbred C57BL
- Urinary Bladder/drug effects
- Urinary Bladder/physiopathology
- Urodynamics/drug effects
- Mice
- Disease Models, Animal
- Ganglia, Spinal/drug effects
- Ganglia, Spinal/metabolism
- Ganglia, Spinal/physiopathology
- Receptors, Cannabinoid/metabolism
- Receptors, Cannabinoid/drug effects
- Enzyme Inhibitors/pharmacology
- Endocannabinoids/metabolism
- Cytokines/metabolism
- Urinary Bladder, Neurogenic/drug therapy
- Urinary Bladder, Neurogenic/physiopathology
- Urinary Bladder, Neurogenic/etiology
- Lower Urinary Tract Symptoms/drug therapy
- Lower Urinary Tract Symptoms/physiopathology
- Lower Urinary Tract Symptoms/etiology
- Carbamates
- Succinimides
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Affiliation(s)
- Kang Jun Cho
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- Department of Urology, Bucheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Mamoru Hashimoto
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- Department of Urology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
| | - Sergei Karnup
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Kanako Matsuoka
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Tadanobu Kamijo
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Joon Chul Kim
- Department of Urology, Bucheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jun Sung Koh
- Department of Urology, Bucheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Naoki Yoshimura
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
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Katsimperis S, Kapriniotis K, Manolitsis I, Bellos T, Angelopoulos P, Juliebø-Jones P, Somani B, Skolarikos A, Tzelves L. Early investigational agents for the treatment of benign prostatic hyperplasia'. Expert Opin Investig Drugs 2024; 33:359-370. [PMID: 38421373 DOI: 10.1080/13543784.2024.2326023] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Accepted: 02/28/2024] [Indexed: 03/02/2024]
Abstract
INTRODUCTION Benign prostatic hyperplasia (BPH), as a clinical entity that affects many people, has always been in the forefront of interest among researchers, pharmaceutical companies, and physicians. Patients with BPH exhibit a diverse range of symptoms, while current treatment options can occasionally cause adverse events. All the aforementioned have led to an increased demand for more effective treatment options. AREAS COVERED This review summarizes the outcomes of new medications used in a pre-clinical and clinical setting for the management of male lower urinary tract symptoms (LUTS)/BPH and provides information about ongoing trials and future directions in the management of this condition. More specifically, sheds light upon drug categories, such as reductase‑adrenoceptor antagonists, drugs interfering with the nitric oxide (NO)/cyclic guanosine monophosphate (GMP) signaling pathway, onabotulinumtoxinA, vitamin D3 (calcitriol) analogues, selective cannabinoid (CB) receptor agonists, talaporfin sodium, inhibitor of transforming growth factor beta 1 (TGF-β1), drugs targeting the hormonal control of the prostate, phytotherapy, and many more. EXPERT OPINION Clinical trials are being conducted on a number of new medications that may emerge as effective therapeutic alternatives in the coming years.
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Affiliation(s)
- Stamatios Katsimperis
- 2nd University Department of Urology, Sismanoglio Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | | | - Ioannis Manolitsis
- 2nd University Department of Urology, Sismanoglio Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Themistoklis Bellos
- 2nd University Department of Urology, Sismanoglio Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Panagiotis Angelopoulos
- 2nd University Department of Urology, Sismanoglio Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Patrick Juliebø-Jones
- Department of Urology, Haukeland University Hospital, Bergen, Norway
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
| | - Bhaskar Somani
- Department of Urology, University Hospital Southampton, Southampton, UK
| | - Andreas Skolarikos
- 2nd University Department of Urology, Sismanoglio Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Lazaros Tzelves
- 2nd University Department of Urology, Sismanoglio Hospital, National and Kapodistrian University of Athens, Athens, Greece
- Department of Urology, University College of London Hospitals (UCLH), London, UK
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Mechsner S. [Holistic treatment of endometriosis]. Schmerz 2023; 37:437-447. [PMID: 37626190 DOI: 10.1007/s00482-023-00747-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 06/26/2023] [Accepted: 07/04/2023] [Indexed: 08/27/2023]
Abstract
BACKGROUND The pain phenomena caused by endometriosis are manifold. In addition to nociceptive pain there is also a nociplastic reaction with central sensitization. Atypical symptoms, such as acyclic lower abdominal pain, radiating pain, nonspecific bladder and intestinal complaints or even depression increasingly occur in addition to the classical cyclic complaints, such as severe dysmenorrhea, cyclic lower abdominal pain, dyspareunia, dysuria and dyschezia. Due to the diffuse range of symptoms, affected patients often consult not just gynecologists but also specialists from other disciplines (internal medicine, gastroenterology, orthopedics, pain therapy, psychology etc.). OBJECTIVE The complexity of endometriosis is presented. The resulting approaches to multimodal interdisciplinary holistic treatment are described. RESULTS Interdisciplinary concepts should be involved in the optimal treatment of endometriosis patients along with hormonal and surgical treatment, mostly under the supervision of a gynecologist and pain management, dietary changes, psychological support and physiotherapeutic management should also be included. This article provides an overview of possible treatment strategies for chronic symptomatic endometriosis. CONCLUSION Based on multimodal treatment strategies and regarding the complex pathophysiological alterations of this disease, the complex complaints that significantly impair the quality of life of endometriosis patients can be greatly improved.
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Affiliation(s)
- Sylvia Mechsner
- Klinik für Gynäkologie, Endometriosezentrum Charité, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Deutschland.
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Michel MC, Cardozo L, Chermansky CJ, Cruz F, Igawa Y, Lee KS, Sahai A, Wein AJ, Andersson KE. Current and Emerging Pharmacological Targets and Treatments of Urinary Incontinence and Related Disorders. Pharmacol Rev 2023; 75:554-674. [PMID: 36918261 DOI: 10.1124/pharmrev.121.000523] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 01/23/2023] [Accepted: 01/24/2023] [Indexed: 03/16/2023] Open
Abstract
Overactive bladder syndrome with and without urinary incontinence and related conditions, signs, and disorders such as detrusor overactivity, neurogenic lower urinary tract dysfunction, underactive bladder, stress urinary incontinence, and nocturia are common in the general population and have a major impact on the quality of life of the affected patients and their partners. Based on the deliberations of the subcommittee on pharmacological treatments of the 7th International Consultation on Incontinence, we present a comprehensive review of established drug targets in the treatment of overactive bladder syndrome and the aforementioned related conditions and the approved drugs used in its treatment. Investigational drug targets and compounds are also reviewed. We conclude that, despite a range of available medical treatment options, a considerable medical need continues to exist. This is largely because the existing treatments are symptomatic and have limited efficacy and/or tolerability, which leads to poor long-term adherence. SIGNIFICANCE STATEMENT: Urinary incontinence and related disorders are prevalent in the general population. While many treatments have been approved, few patients stay on long-term treatment despite none of them being curative. This paper provides a comprehensive discussion of existing and emerging treatment options for various types of incontinence and related disorders.
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Affiliation(s)
- Martin C Michel
- Department of Pharmacology, University Medical Center, Johannes Gutenberg University, Mainz, Germany (M.C.M.); Department of Urogynaecology, King's College Hospital, London, UK (L.C.); Department of Urology, Magee Women's Hospital, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania (C.J.C.); Department of Urology, Faculty of Medicine of University of Porto, Hospital São João and i3S Institute for Innovation and Investigation in Health, Porto, Portugal (F.C.); Department of Urology, Nagano Prefectural Shinshu Medical Center, Suzaka, Japan (Y.I.); Department of Urology Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea (K-S.L.); Guy's Hospital and King's College London, London, UK (A.S.); Dept. of Urology, Perlman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (A.J.W.); Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina (A.J.W.); and Institute for Laboratory Medicine, Lund University, Lund, Sweden (K-E.A.)
| | - Linda Cardozo
- Department of Pharmacology, University Medical Center, Johannes Gutenberg University, Mainz, Germany (M.C.M.); Department of Urogynaecology, King's College Hospital, London, UK (L.C.); Department of Urology, Magee Women's Hospital, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania (C.J.C.); Department of Urology, Faculty of Medicine of University of Porto, Hospital São João and i3S Institute for Innovation and Investigation in Health, Porto, Portugal (F.C.); Department of Urology, Nagano Prefectural Shinshu Medical Center, Suzaka, Japan (Y.I.); Department of Urology Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea (K-S.L.); Guy's Hospital and King's College London, London, UK (A.S.); Dept. of Urology, Perlman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (A.J.W.); Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina (A.J.W.); and Institute for Laboratory Medicine, Lund University, Lund, Sweden (K-E.A.)
| | - Christopher J Chermansky
- Department of Pharmacology, University Medical Center, Johannes Gutenberg University, Mainz, Germany (M.C.M.); Department of Urogynaecology, King's College Hospital, London, UK (L.C.); Department of Urology, Magee Women's Hospital, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania (C.J.C.); Department of Urology, Faculty of Medicine of University of Porto, Hospital São João and i3S Institute for Innovation and Investigation in Health, Porto, Portugal (F.C.); Department of Urology, Nagano Prefectural Shinshu Medical Center, Suzaka, Japan (Y.I.); Department of Urology Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea (K-S.L.); Guy's Hospital and King's College London, London, UK (A.S.); Dept. of Urology, Perlman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (A.J.W.); Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina (A.J.W.); and Institute for Laboratory Medicine, Lund University, Lund, Sweden (K-E.A.)
| | - Francisco Cruz
- Department of Pharmacology, University Medical Center, Johannes Gutenberg University, Mainz, Germany (M.C.M.); Department of Urogynaecology, King's College Hospital, London, UK (L.C.); Department of Urology, Magee Women's Hospital, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania (C.J.C.); Department of Urology, Faculty of Medicine of University of Porto, Hospital São João and i3S Institute for Innovation and Investigation in Health, Porto, Portugal (F.C.); Department of Urology, Nagano Prefectural Shinshu Medical Center, Suzaka, Japan (Y.I.); Department of Urology Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea (K-S.L.); Guy's Hospital and King's College London, London, UK (A.S.); Dept. of Urology, Perlman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (A.J.W.); Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina (A.J.W.); and Institute for Laboratory Medicine, Lund University, Lund, Sweden (K-E.A.)
| | - Yasuhiko Igawa
- Department of Pharmacology, University Medical Center, Johannes Gutenberg University, Mainz, Germany (M.C.M.); Department of Urogynaecology, King's College Hospital, London, UK (L.C.); Department of Urology, Magee Women's Hospital, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania (C.J.C.); Department of Urology, Faculty of Medicine of University of Porto, Hospital São João and i3S Institute for Innovation and Investigation in Health, Porto, Portugal (F.C.); Department of Urology, Nagano Prefectural Shinshu Medical Center, Suzaka, Japan (Y.I.); Department of Urology Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea (K-S.L.); Guy's Hospital and King's College London, London, UK (A.S.); Dept. of Urology, Perlman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (A.J.W.); Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina (A.J.W.); and Institute for Laboratory Medicine, Lund University, Lund, Sweden (K-E.A.)
| | - Kyu-Sung Lee
- Department of Pharmacology, University Medical Center, Johannes Gutenberg University, Mainz, Germany (M.C.M.); Department of Urogynaecology, King's College Hospital, London, UK (L.C.); Department of Urology, Magee Women's Hospital, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania (C.J.C.); Department of Urology, Faculty of Medicine of University of Porto, Hospital São João and i3S Institute for Innovation and Investigation in Health, Porto, Portugal (F.C.); Department of Urology, Nagano Prefectural Shinshu Medical Center, Suzaka, Japan (Y.I.); Department of Urology Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea (K-S.L.); Guy's Hospital and King's College London, London, UK (A.S.); Dept. of Urology, Perlman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (A.J.W.); Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina (A.J.W.); and Institute for Laboratory Medicine, Lund University, Lund, Sweden (K-E.A.)
| | - Arun Sahai
- Department of Pharmacology, University Medical Center, Johannes Gutenberg University, Mainz, Germany (M.C.M.); Department of Urogynaecology, King's College Hospital, London, UK (L.C.); Department of Urology, Magee Women's Hospital, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania (C.J.C.); Department of Urology, Faculty of Medicine of University of Porto, Hospital São João and i3S Institute for Innovation and Investigation in Health, Porto, Portugal (F.C.); Department of Urology, Nagano Prefectural Shinshu Medical Center, Suzaka, Japan (Y.I.); Department of Urology Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea (K-S.L.); Guy's Hospital and King's College London, London, UK (A.S.); Dept. of Urology, Perlman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (A.J.W.); Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina (A.J.W.); and Institute for Laboratory Medicine, Lund University, Lund, Sweden (K-E.A.)
| | - Alan J Wein
- Department of Pharmacology, University Medical Center, Johannes Gutenberg University, Mainz, Germany (M.C.M.); Department of Urogynaecology, King's College Hospital, London, UK (L.C.); Department of Urology, Magee Women's Hospital, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania (C.J.C.); Department of Urology, Faculty of Medicine of University of Porto, Hospital São João and i3S Institute for Innovation and Investigation in Health, Porto, Portugal (F.C.); Department of Urology, Nagano Prefectural Shinshu Medical Center, Suzaka, Japan (Y.I.); Department of Urology Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea (K-S.L.); Guy's Hospital and King's College London, London, UK (A.S.); Dept. of Urology, Perlman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (A.J.W.); Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina (A.J.W.); and Institute for Laboratory Medicine, Lund University, Lund, Sweden (K-E.A.)
| | - Karl-Erik Andersson
- Department of Pharmacology, University Medical Center, Johannes Gutenberg University, Mainz, Germany (M.C.M.); Department of Urogynaecology, King's College Hospital, London, UK (L.C.); Department of Urology, Magee Women's Hospital, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania (C.J.C.); Department of Urology, Faculty of Medicine of University of Porto, Hospital São João and i3S Institute for Innovation and Investigation in Health, Porto, Portugal (F.C.); Department of Urology, Nagano Prefectural Shinshu Medical Center, Suzaka, Japan (Y.I.); Department of Urology Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea (K-S.L.); Guy's Hospital and King's College London, London, UK (A.S.); Dept. of Urology, Perlman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (A.J.W.); Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina (A.J.W.); and Institute for Laboratory Medicine, Lund University, Lund, Sweden (K-E.A.)
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Zapała Ł, Niemczyk G, Zapała P, Wdowiak A, Bojar I, Kluz T, Szopa A, Serefko A, Radziszewski P, Wróbel A. The Cannabinoid Ligand Arachidonyl-2'-Chloroethylamide (ACEA) Ameliorates Depressive and Overactive Bladder Symptoms in a Corticosterone-Induced Female Wistar Rat Model. Int J Mol Sci 2023; 24:ijms24043820. [PMID: 36835228 PMCID: PMC9963199 DOI: 10.3390/ijms24043820] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 02/07/2023] [Accepted: 02/13/2023] [Indexed: 02/17/2023] Open
Abstract
There is growing need to increase the knowledge on the cannabinoid ligands in the treatment of overactive bladder. Among potential candidates, arachidonyl-2'-chloroethylamide (ACEA), a selective cannabinoid CB1 receptor agonist is proposed. The aim of this paper was to determine if ACEA, a selective cannabinoid CB1 receptor agonist, could reverse the effects of corticosterone (CORT), characteristic of depressive and bladder overactivity potential. The animals (48 female rats) were divided into four groups: I-control, II-received CORT, III-received ACEA, and IV-received the combination of CORT and ACEA. The conscious cystometry, forced swim test (FST), and locomotor activity measurements were performed 3 days after the last dose of ACEA, followed by ELISA measurements. In group IV, ACEA restored urodynamic parameters that were altered by CORT. CORT prolonged the immobility time in FST and the values were lowered by ACEA. ACEA normalized the expression of c-Fos in all the analyzed central micturition centers (group IV vs. group II). ACEA restored the CORT-induced changes in the biomarkers in urine (BDNF, NGF), bladder detrusor (VAChT, Rho kinase), bladder urothelium (CGRP, ATP, CRF, OCT-3, TRPV1), and hippocampus (TNF-α, IL-1β and Il-6, CRF, IL-10, BDNF, NGF). In conclusion, ACEA was proven to reverse CORT-induced changes in both cystometric and biochemical parameters that are determinants of OAB/depression, which represents an example of an existing link between OAB and depression via cannabinoid receptors.
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Affiliation(s)
- Łukasz Zapała
- Clinic of General, Oncological and Functional Urology, Medical University of Warsaw, Lindleya 4, 02-005 Warsaw, Poland
- Correspondence: (Ł.Z.); (A.W.)
| | - Grzegorz Niemczyk
- Clinic of General, Oncological and Functional Urology, Medical University of Warsaw, Lindleya 4, 02-005 Warsaw, Poland
| | - Piotr Zapała
- Clinic of General, Oncological and Functional Urology, Medical University of Warsaw, Lindleya 4, 02-005 Warsaw, Poland
| | - Artur Wdowiak
- Chair of Obstetrics and Gynecology, Faculty of Health Sciences, Medical University of Lublin, 4-6 Staszica St., 20-081 Lublin, Poland
| | - Iwona Bojar
- Department of Women’s Health, Institute of Rural Health in Lublin, Ul. Jaczewskiego 2, 20-090 Lublin, Poland
| | - Tomasz Kluz
- Department of Gynecology, Gynecology Oncology and Obstetrics, Institute of Medical Sciences, Medical College of Rzeszow University, 16c Rejtana Street, 35-959 Rzeszow, Poland
| | - Aleksandra Szopa
- Department of Clinical Pharmacy and Pharmaceutical Care, Faculty of Pharmacy, Medical University of Lublin, 1 Chodźki Street, 20-093 Lublin, Poland
| | - Anna Serefko
- Department of Clinical Pharmacy and Pharmaceutical Care, Faculty of Pharmacy, Medical University of Lublin, 1 Chodźki Street, 20-093 Lublin, Poland
| | - Piotr Radziszewski
- Clinic of General, Oncological and Functional Urology, Medical University of Warsaw, Lindleya 4, 02-005 Warsaw, Poland
| | - Andrzej Wróbel
- Second Department of Gynecology, Medical University of Lublin, Jaczewskiego 8, 20-090 Lublin, Poland
- Correspondence: (Ł.Z.); (A.W.)
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7
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İlhan SÖ, Fincan GSÖ, Okçay Y, Koç DS, Aşkın Cİ, Kibar AK, Vural İM, Sarıoğlu Y. Enhancing effect of nicotine on electrical field stimulation elicited contractile responses in isolated rabbit bladder straight muscle; the role of cannabinoid and vanilloid receptors. Turk J Med Sci 2022; 52:1814-1820. [PMID: 36945969 PMCID: PMC10390188 DOI: 10.55730/1300-0144.5527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Accepted: 09/10/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Nicotine acts as an agonist of nicotinic acetylcholine receptors (nAChR). These receptors belong to a superfamily of ligand-gated ion channels. We previously demonstrated that nicotine increased electrical field stimulation (EFS)-induced contractile or relaxation responses, possibly by facilitating neurotransmitter release from nerve terminals in various rabbit tissues. Studies have shown that there is an interaction between the endocannabinoid and nicotinic systems. This study aimed to investigate the interaction between nicotine and the endocannabinoid system in the rabbit urine bladder and also investigate the enhancing effect of nicotine on EFS-induced contractile responses in rabbit isolated bladder smooth muscle and its interaction with the endocannabinoid system. METHODS The New Zealand albino male adult rabbits were used for this study. Following scarification, the urine bladder was rapidly excised, and then uniform strips were prepared. Each strip was mounted under 1 g isometric resting tension in an organ bath containing 20 mL of Krebs-Henseleit solution. After obtaining EFS-induced contractile responses, 10-4 M concentrations of nicotine were applied to the preparations, and EFS was stopped after 5 stimulations. Following washing, the same experimental procedure was performed with the same tissue in the presence of AM251 (a cannabinoid CB1R antagonist, 10-6 M), AM630 (a cannabinoid CB2R antagonist, 10-6 M), and capsazepine (a vanilloid receptor antagonist, 3 × 10-6 M). RESULTS Nicotine enhanced the EFS-induced contraction responses by 17.16% ± 2.81% at a 4-Hz stimulation frequency. Cannabinoid receptor antagonists AM251 and AM630 reduced this increasing effect of nicotine although it was not significant and vanilloid receptor antagonist capsazepine did not significantly alter the nicotines' effect. DISCUSSION These results show that enhancing effect of nicotine in the smooth muscle of the rabbit bladder, even though it was not significant endocannabinoid system possibly have a role in nicotines' effect.
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Affiliation(s)
- Sevil Özger İlhan
- Department of Medical Pharmacology, Faculty of Medicine, Gazi University, Ankara, Turkey
| | | | - Yağmur Okçay
- Department of Pharmacology, Gülhane Faculty of Pharmacy, University of Health Sciences, Ankara, Turkey
| | - Derya Sebile Koç
- Department of Medical Pharmacology, Faculty of Medicine, Gazi University, Ankara, Turkey
| | - Celil İlker Aşkın
- Department of Medical Pharmacology, Faculty of Medicine, Gazi University, Ankara, Turkey
| | - Ayşe Kübra Kibar
- Department of Medical Pharmacology, Faculty of Medicine, Gazi University, Ankara, Turkey
| | - İsmail Mert Vural
- Department of Pharmacology, Gülhane Faculty of Pharmacy, University of Health Sciences, Ankara, Turkey
| | - Yusuf Sarıoğlu
- Department of Medical Pharmacology, Faculty of Medicine, İstinye University, İstanbul, Turkey
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8
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Cannabis Use Disorder in the Setting of Primary Total Hip Arthroplasty: Understanding the Epidemiology, Demographic Characteristics, and Inpatient Postoperative Outcomes. J Am Acad Orthop Surg 2022; 30:321-328. [PMID: 35213453 DOI: 10.5435/jaaos-d-21-00976] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 01/21/2022] [Indexed: 02/01/2023] Open
Abstract
INTRODUCTION Cannabis use is expected to increase in the context of its decriminalization and legalization in several states. The purpose of this study was to report on the epidemiologic and demographic characteristics and inpatient postoperative outcomes of patients with cannabis use disorder (CUD) undergoing primary total hip arthroplasty (THA). METHODS The National Inpatient Sample registry was used to identify patients undergoing THA between 2006 and 2015. Patients were stratified into groups with and without CUD. Epidemiology, comorbidity, and outcomes data were comparatively analyzed between these two groups. RESULTS A total of 2,838,742 THAs were performed during the study period. The prevalence of CUD significantly increased from 0.10% in 2006 to 0.39% in 2015 (P < 0.0001). Patients with CUD were significantly younger, more likely to be male, had higher rates of Medicaid insurance and were more likely to be non-Hispanic Black and less likely to be non-Hispanic White when compared with the control group. When comparing patients with and without CUD, there was no significant difference in the composite any complication variable and no significant difference in seven of eight individual in-hospital complications assessed, with the exception being higher genitourinary complications in the CUD group. There were no significant differences in discharge disposition or length of stay. DISCUSSION Although CUD is significantly associated with various demographic, comorbidity, and hospital characteristics, it is not significantly associated with in-hospital complications, discharge disposition, and length of stay outcomes in the immediate in-hospital, postoperative period. It is critical for clinicians and public health professionals to understand the characteristics and expected inpatient outcomes of this evolving population of patients with CUD undergoing THA, particularly in the context of widespread legalization. LEVEL OF EVIDENCE Level III.
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9
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O’Brien K. Cannabidiol (CBD) in Cancer Management. Cancers (Basel) 2022; 14:cancers14040885. [PMID: 35205633 PMCID: PMC8869992 DOI: 10.3390/cancers14040885] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 01/28/2022] [Accepted: 02/05/2022] [Indexed: 12/23/2022] Open
Abstract
Simple Summary Cannabidiol (CBD) is one of the main constituents of the plant Cannabis sativa. Surveys suggest that medicinal cannabis is popular amongst people diagnosed with cancer. CBD is one of the key constituents of cannabis, and does not have the potentially intoxicating effects that tetrahydrocannabinol (THC), the other key phytocannabinoid has. Research indicates the CBD may have potential for the treatment of cancer, including the symptoms and signs associated with cancer and its treatment. Preclinical research suggests CBD may address many of the pathways involved in the pathogenesis of cancers. Preclinical and clinical research also suggests some evidence of efficacy, alone or in some cases in conjunction with tetrahydrocannabinol (THC, the other key phytocannabinoid in cannabis), in treating cancer-associated pain, anxiety and depression, sleep problems, nausea and vomiting, and oral mucositis that are associated with cancer and/or its treatment. Studies also suggest that CBD may enhance orthodox treatments with chemotherapeutic agents and radiation therapy and protect against neural and organ damage. CBD shows promise as part of an integrative approach to the management of cancer. Abstract The plant Cannabis sativa has been in use medicinally for several thousand years. It has over 540 metabolites thought to be responsible for its therapeutic effects. Two of the key phytocannabinoids are cannabidiol (CBD) and tetrahydrocannabinol (THC). Unlike THC, CBD does not have potentially intoxicating effects. Preclinical and clinical research indicates that CBD has a wide range of therapeutic effects, and many of them are relevant to the management of cancer. In this article, we explore some of the potential mechanisms of action of CBD in cancer, and evidence of its efficacy in the integrative management of cancer including the side effects associated with its treatment, demonstrating its potential for integration with orthodox cancer care.
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Affiliation(s)
- Kylie O’Brien
- Adelaide Campus, Torrens University, Adelaide, SA 5000, Australia;
- NICM Health Research Centre, Western Sydney University, Westmead, Sydney, NSW 2145, Australia
- Releaf Group Ltd., St Kilda, VIC 3182, Australia
- International College of Cannabinoid Medicine, iccm.co, London N1 7GU, UK
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10
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Sultana S, Berger G, Lehmann C. Components of the Endogenous Cannabinoid System as Potential Biomarkers for Interstitial Cystitis/Bladder Pain Syndrome. Diagnostics (Basel) 2021; 12:diagnostics12010019. [PMID: 35054185 PMCID: PMC8775086 DOI: 10.3390/diagnostics12010019] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 12/17/2021] [Accepted: 12/20/2021] [Indexed: 12/24/2022] Open
Abstract
Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic condition causing bladder pressure and pain. The condition is of unknown etiology and is often accompanied by other symptoms, including chronic pelvic pain, increased urinary urgency, and frequency. There is no definitive diagnosis for IC/BPS, and treatment options are currently limited to physical therapy and medications to help alleviate symptoms. The endogenous cannabinoid system (ECS) is an important regulator of numerous physiological systems, including the urinary system. Modulations of the ECS have been shown to be beneficial for IC/BPS-associated pain and inflammation in rodents. As an attempt to identify potential biomarkers for IC/BPS, we reviewed experimental studies where the components of the ECS have been quantified in experimental models of IC/BPS. Further investigations using well-defined animal models and patients’ data are required to obtain stronger evidence regarding the potential for ECS components to be definitive biomarkers for IC/BPS.
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Affiliation(s)
- Saki Sultana
- Department of Pharmacology, Dalhousie University, Halifax, NS B3H 4R2, Canada; (G.B.); (C.L.)
- Correspondence:
| | - Geraint Berger
- Department of Pharmacology, Dalhousie University, Halifax, NS B3H 4R2, Canada; (G.B.); (C.L.)
- Department of Anesthesia, Pain Management and Perioperative Medicine, Dalhousie University, Halifax, NS B3H 4R2, Canada
| | - Christian Lehmann
- Department of Pharmacology, Dalhousie University, Halifax, NS B3H 4R2, Canada; (G.B.); (C.L.)
- Department of Anesthesia, Pain Management and Perioperative Medicine, Dalhousie University, Halifax, NS B3H 4R2, Canada
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Noguchi K, Kadekawa K, Nishijima S, Sakanashi M, Okitsu-Sakurayama S, Higa-Nakamine S, Yamamoto H, Sugaya K. Phenotypic Characterization of the Endocannabinoid-Degrading Enzyme Alpha/Beta-Hydrolase Domain 6 Knockout Rat. Cannabis Cannabinoid Res 2021; 7:179-187. [PMID: 34468198 PMCID: PMC9070737 DOI: 10.1089/can.2021.0011] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Introduction: Alpha/beta-hydrolase domain 6 (ABHD6) is an enzyme that hydrolyzes 2-arachidonoylglycerol, a high-efficiency endogenous cannabinoid. Although the endocannabinoid system has been suggested to be involved in regulation of bladder function, the roles of ABHD6 in the control of micturition remain unknown. To elucidate the physiological and pathological roles of ABHD6 in vivo, we examined phenotypes of ABHD6 knockout rats (Abhd6-/-) generated by clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated proteins system. Materials and Methods: Age-matched knockout and wild-type (WT) rats of both sexes were used. Results: Expression of ABHD6, assessed by quantitative real-time polymerase chain reaction and Western blot analysis, was clearly diminished in Abhd6-/- rats compared with WT rats. Mutant rats had a normal appearance, and the body weight and food consumption were similar to those of WT rats. The interval between bladder contractions assessed by continuous cystometry was significantly shorter in ABHD6 knockout rats than in WT rats when the bladder was stimulated with acetic acid. Mechanical paw withdrawal thresholds measured by von Frey testing were significantly lowered in the knockout rats than in WT rats. The plasma levels of prostaglandin E2 (PGE2) and the stable metabolite of PGE2 in Abhd6-/- rats were twice as high as that in WT rats. Conclusions: Deletion of the ABHD6 gene in rats causes more frequent urination in the stimulated bladder and hyperalgesia to non-noxious mechanical stimuli along with increased plasma PGE2.
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Affiliation(s)
| | | | | | | | - Shiho Okitsu-Sakurayama
- Department of Biochemistry, Graduate School of Medicine, University of the Ryukyus, Nakagami-gun, Japan
| | - Sayomi Higa-Nakamine
- Department of Biochemistry, Graduate School of Medicine, University of the Ryukyus, Nakagami-gun, Japan
| | - Hideyuki Yamamoto
- Department of Biochemistry, Graduate School of Medicine, University of the Ryukyus, Nakagami-gun, Japan
| | - Kimio Sugaya
- Southern Knights' Laboratory Co., Ltd., Chatan, Japan
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12
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Christie S, Brookes S, Zagorodnyuk V. Endocannabinoids in Bladder Sensory Mechanisms in Health and Diseases. Front Pharmacol 2021; 12:708989. [PMID: 34290614 PMCID: PMC8287826 DOI: 10.3389/fphar.2021.708989] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Accepted: 06/23/2021] [Indexed: 01/23/2023] Open
Abstract
The recent surge in research on cannabinoids may have been fueled by changes in legislation in several jurisdictions, and by approval for the use of cannabinoids for treatment of some chronic diseases. Endocannabinoids act largely, but not exclusively on cannabinoid receptors 1 and 2 (CBR1 and CBR2) which are expressed in the bladder mainly by the urothelium and the axons and endings of motor and sensory neurons. A growing body of evidence suggests that endocannabinoid system constitutively downregulates sensory bladder function during urine storage and micturition, under normal physiological conditions. Similarly, exogenous cannabinoid agonists have potent modulatory effects, as do inhibitors of endocannabinoid inactivation. Results suggest a high potential of cannabinoids to therapeutically ameliorate lower urinary tract symptoms in overactive bladder and painful bladder syndromes. At least part of this may be mediated via effects on sensory nerves, although actions on efferent nerves complicate interpretation. The sensory innervation of bladder is complex with at least eight classes identified. There is a large gap in our knowledge of the effects of endocannabinoids and synthetic agonists on different classes of bladder sensory neurons. Future studies are needed to reveal the action of selective cannabinoid receptor 2 agonists and/or peripherally restricted synthetic cannabinoid receptor 1 agonists on bladder sensory neurons in animal models of bladder diseases. There is significant potential for these novel therapeutics which are devoid of central nervous system psychotropic actions, and which may avoid many of the side effects of current treatments for overactive bladder and painful bladder syndromes.
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Affiliation(s)
| | | | - Vladimir Zagorodnyuk
- Discipline of Human Physiology, College of Medicine and Public Health, Flinders Health and Medical Research Institute, Flinders University, Adelaide, SA, Australia
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13
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Stairs J, Maguire F, Lehmann C, Cox A. Cannabinoid Therapy in Female Pelvic Medicine and Reconstructive Surgery: Current Evidence and Future Directions. CURRENT BLADDER DYSFUNCTION REPORTS 2021. [DOI: 10.1007/s11884-021-00632-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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Mechsner S. [Management of endometriosis pain : Stage-based treatment strategies and clinical experience]. Schmerz 2021; 35:159-171. [PMID: 33704582 DOI: 10.1007/s00482-021-00543-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 01/29/2021] [Accepted: 02/02/2021] [Indexed: 12/17/2022]
Abstract
BACKGROUND Endometriosis is associated with various types of intense pain. In addition to nociceptive pain, there is also a nociplastic reaction with central sensitization. Atypical symptoms such as acyclic lower abdominal pain, radiating pain, non-specific bladder and intestinal complaints or even depression are frequent as are classic cyclical complaints such as severe dysmenorrhea, cyclical lower abdominal pain, dyspareunia, dysuria and dyschezia. In cases of a diverse range of symptoms, patients often consult not just gynecologists but specialists from other disciplines (e.g., internal medicine, gastroenterology, orthopedics, pain therapy, psychology). AIMS Overview about the pathophysiology and complexity of the disease and the resulting treatment options. A multimodal interdisciplinary concept might be able to take into consideration all aspects of the complex disease. METHODS Interdisciplinary concepts should be involved in the treatment of endometriosis patients along with hormonal and surgical therapy, which are generally under the supervision of a gynecologist. Pain management, dietary changes, psychological support, as well as physiotherapy should be included. The present article is intended to provide an overview of possible treatment strategies for chronic, symptomatic endometriosis. CONCLUSION The use of multimodal treatment strategies regarding the complex pathophysiological aspects of this disease might be helpful in significantly improving the quality of life of endometriosis patients.
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Affiliation(s)
- Sylvia Mechsner
- Klinik für Gynäkologie, Endometriosezentrum Charité, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Deutschland.
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15
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Nabata KJ, Tse EK, Nightingale TE, Lee AH, Eng JJ, Querée M, Walter M, Krassioukov AV. The Therapeutic Potential and Usage Patterns of Cannabinoids in People with Spinal Cord Injuries: A Systematic Review. Curr Neuropharmacol 2021; 19:402-432. [PMID: 32310048 PMCID: PMC8033968 DOI: 10.2174/1570159x18666200420085712] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Revised: 03/12/2020] [Accepted: 04/15/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND People with spinal cord injuries (SCI) commonly experience pain and spasticity; limitations of current treatments have generated interest in cannabis as a possible therapy. OBJECTIVES We conducted this systematic review to: 1) examine usage patterns and reasons for cannabinoid use, and 2) determine the treatment efficacy and safety of cannabinoid use in people with SCI. METHODS PubMed, Embase, Web of Science and Cumulative Index to Nursing and Allied Health Literature databases were queried for keywords related to SCI and cannabinoids. RESULTS 7,232 studies were screened, and 34 were included in this systematic review. Though 26 studies addressed cannabinoid usage, only 8 investigated its therapeutic potential on outcomes such as pain and spasticity. The most common method of use was smoking. Relief of pain, spasticity and recreation were the most common reasons for use. A statistically significant reduction of pain and spasticity was observed with cannabinoid use in 83% and 100% of experimental studies, respectively. However, on examination of randomized control trials (RCTs) alone, effect sizes ranged from - 0.82 to 0.83 for pain and -0.95 to 0.09 for spasticity. Cannabinoid use was associated with fatigue and cognitive deficits. CONCLUSION Current evidence suggests that cannabinoids may reduce pain and spasticity in people with SCI, but its effect magnitude and clinical significance are unclear. Existing information is lacking on optimal dosage, method of use, composition and concentration of compounds. Long-term, double-blind, RCTs, assessing a wider range of outcomes should be conducted to further understand the effects of cannabinoid use in people with SCI.
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Affiliation(s)
| | | | | | | | | | | | | | - Andrei V. Krassioukov
- Address correspondence to this author at the International Collaboration On Repair Discoveries (ICORD), University of British Columbia (UBC), Vancouver, Canada; E-mail:
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16
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Lopez SR, Mangır N. Current standard of care in treatment of bladder pain syndrome/interstitial cystitis. Ther Adv Urol 2021; 13:17562872211022478. [PMID: 34178118 PMCID: PMC8202321 DOI: 10.1177/17562872211022478] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 05/15/2021] [Indexed: 12/30/2022] Open
Abstract
Bladder pain syndrome/interstitial cystitis (BPS/IC) is a debilitating, systemic pain syndrome with a cardinal symptom of bladder related pain with associated systemic symptoms. It is characterized by an inflammation that partially or completely destroys the mucus membrane and can extend into the muscle layer; however, the etiology and pathogenesis is still enigmatic. It has been suggested that mast cell activation, defects in the glycosaminoglycan layer, non-functional proliferation of bladder epithelial cells, neurogenic inflammation, microvascular abnormalities in the submucosal layer, autoimmunity and infectious causes may cause BPS/IC. Available treatment options include general relaxation techniques, patient education, behavioral treatments, physical therapy, multimodal pain therapy, oral (amitriptyline, cimetidine, hydroxyzine) and intravesical treatments (heparin, lidocaine, hyaluronic acid and chondroitin sulfate), hydrodistension and other more invasive treatments. Available treatments are mostly not based on a high level of evidence. Lack of understanding of disease mechanisms has resulted in lack of targeted therapies on this area and a wealth of empirical approaches with usually inadequate efficacy. The aim of this article is to review the available evidence on the pathophysiological mechanisms of BPS/IC as they relate to available treatment options.
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Affiliation(s)
| | - Naşide Mangır
- Department of Urology, Consultant Urologist and Clinical Lecturer in Urology, Hacettepe University School of Medicine, Sıhhiye, Ankara 06100, Turkey
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Cannabinoids in Urology. Which Benign Conditions Might They Be Appropriate to Treat: A Systematic Review. Urology 2020; 148:8-25. [PMID: 33129871 DOI: 10.1016/j.urology.2020.10.024] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 10/14/2020] [Accepted: 10/15/2020] [Indexed: 11/24/2022]
Abstract
There is growing evidence suggesting cannabinoids may provide suitable alternatives to conventional treatments in an increasing number of clinical settings. This review evaluates how cannabinoids are used to treat certain benign urological pathologies and to clarify the clinical value of this data. This review includes 62 papers and was undertaken per PRISMA's guidelines, it evidences the therapeutic potential of cannabinoids in the management of specific benign urological diseases, most notably neurogenic bladder dysfunction (clinical studies), renal disease (animal studies), and interstitial cystitis (animal studies). However, whilst cannabinoids are increasingly used, they cannot be considered reliable alternatives to more recognised treatments.
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18
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Vago R, Ravelli A, Bettiga A, Casati S, Lavorgna G, Benigni F, Salonia A, Montorsi F, Orioli M, Ciuffreda P, Ottria R. Urine Endocannabinoids as Novel Non-Invasive Biomarkers for Bladder Cancer at Early Stage. Cancers (Basel) 2020; 12:cancers12040870. [PMID: 32260109 PMCID: PMC7226386 DOI: 10.3390/cancers12040870] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Revised: 03/12/2020] [Accepted: 04/01/2020] [Indexed: 12/19/2022] Open
Abstract
Due to the involvement of the endocannabinoid system (ECS) in cancer onset and progression and the less studied connection between ECS and bladder cancer, here an evaluation of the ECS modifications associated with bladder cancer is reported. Urine samples were collected from healthy volunteers and patients with bladder cancer at different grades. Endocannabinoids (ECs) and N-acylethanolamides (NAEs) were quantified by HPLC-MS/MS and results normalized for creatinine content. An increase in the urine concentrations of four ECs and NAEs analyzed was observed with a statistically significant increase in the arachidonoylethanolamide (AEA) and stearoylethanoamide (SEA) associated with bladder cancer. Receiver operating characteristic curves built with AEA and SEA data allowed the selection of 160 pg/mL for SEA (area under the curve (AUC) = 0.91, Selectivity (SE) 94%, Specificity (SP) 45%) and 8 pg/mL for AEA (AUC = 0.85, SE 94%, SP 61%) as the best cut-off values. Moreover, data from bladder cancer samples at different grades were derived from The Cancer Genome Atlas, and the expressions of thirteen different components of the “endocannabinoidome” were analyzed. Statistical analysis highlights significant variations in the expression of three enzymes involved in EC and NAE turnover in bladder cancer.
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Affiliation(s)
- Riccardo Vago
- Urological Research Institute, Division of Experimental Oncology, IRCCS San Raffaele Hospital, 20132 Milano, Italy; (R.V.); (A.B.); (G.L.); (F.B.); (A.S.); (F.M.)
- Università Vita-Salute San Raffaele, 20132 Milano, Italy
| | - Alessandro Ravelli
- Dipartimento di Scienze Biomediche, Chirurgiche ed Odontoiatriche, Sezione di Tossicologia Forense, Università degli Studi di Milano, 20133 Milano, Italy; (A.R.); (M.O.)
| | - Arianna Bettiga
- Urological Research Institute, Division of Experimental Oncology, IRCCS San Raffaele Hospital, 20132 Milano, Italy; (R.V.); (A.B.); (G.L.); (F.B.); (A.S.); (F.M.)
- Università Vita-Salute San Raffaele, 20132 Milano, Italy
| | - Silvana Casati
- Dipartimento di Scienze Biomediche e Cliniche L. Sacco, Università degli Studi di Milano, 20157 Milano, Italy; (S.C.); (P.C.)
| | - Giovanni Lavorgna
- Urological Research Institute, Division of Experimental Oncology, IRCCS San Raffaele Hospital, 20132 Milano, Italy; (R.V.); (A.B.); (G.L.); (F.B.); (A.S.); (F.M.)
- Università Vita-Salute San Raffaele, 20132 Milano, Italy
| | - Fabio Benigni
- Urological Research Institute, Division of Experimental Oncology, IRCCS San Raffaele Hospital, 20132 Milano, Italy; (R.V.); (A.B.); (G.L.); (F.B.); (A.S.); (F.M.)
- Università Vita-Salute San Raffaele, 20132 Milano, Italy
| | - Andrea Salonia
- Urological Research Institute, Division of Experimental Oncology, IRCCS San Raffaele Hospital, 20132 Milano, Italy; (R.V.); (A.B.); (G.L.); (F.B.); (A.S.); (F.M.)
- Università Vita-Salute San Raffaele, 20132 Milano, Italy
| | - Francesco Montorsi
- Urological Research Institute, Division of Experimental Oncology, IRCCS San Raffaele Hospital, 20132 Milano, Italy; (R.V.); (A.B.); (G.L.); (F.B.); (A.S.); (F.M.)
- Università Vita-Salute San Raffaele, 20132 Milano, Italy
| | - Marica Orioli
- Dipartimento di Scienze Biomediche, Chirurgiche ed Odontoiatriche, Sezione di Tossicologia Forense, Università degli Studi di Milano, 20133 Milano, Italy; (A.R.); (M.O.)
| | - Pierangela Ciuffreda
- Dipartimento di Scienze Biomediche e Cliniche L. Sacco, Università degli Studi di Milano, 20157 Milano, Italy; (S.C.); (P.C.)
| | - Roberta Ottria
- Dipartimento di Scienze Biomediche e Cliniche L. Sacco, Università degli Studi di Milano, 20157 Milano, Italy; (S.C.); (P.C.)
- Correspondence: ; Tel.: +39-02-5031-9693
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A Novel Alternative in the Treatment of Detrusor Overactivity? In Vivo Activity of O-1602, the Newly Synthesized Agonist of GPR55 and GPR18 Cannabinoid Receptors. Molecules 2020; 25:molecules25061384. [PMID: 32197469 PMCID: PMC7144400 DOI: 10.3390/molecules25061384] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 03/15/2020] [Accepted: 03/17/2020] [Indexed: 02/07/2023] Open
Abstract
The aim of the research was to assess the impact of O-1602—novel GPR55 and GPR18 agonist—in the rat model of detrusor overactivity (DO). Additionally, its effect on the level of specific biomarkers was examined. To stimulate DO, 0.75% retinyl acetate (RA) was administered to female rats’ bladders. O-1602, at a single dose of 0.25 mg/kg, was injected intra-arterially during conscious cystometry. Furthermore, heart rate, blood pressure, and urine production were monitored for 24 h, and the impact of O-1602 on the levels of specific biomarkers was evaluated. An exposure of the urothelium to RA changed cystometric parameters and enhanced the biomarker levels. O-1602 did not affect any of the examined cystometric parameters or levels of biomarkers in control rats. However, the O-1602 injection into animals with RA-induced DO ameliorated the symptoms of DO and caused a reversal in the described changes in the concentration of CGRP, OCT3, BDNF, and NGF to the levels observed in the control, while the values of ERK1/2 and VAChT were significantly lowered compared with the RA-induced DO group, but were still statistically higher than in the control. O-1602 can improve DO, and may serve as a promising novel substance for the pharmacotherapy of bladder diseases.
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Ückert S, Kedia GT, Tsikas D, Simon A, Bannowsky A, Kuczyk MA. Emerging drugs to target lower urinary tract symptomatology (LUTS)/benign prostatic hyperplasia (BPH): focus on the prostate. World J Urol 2019; 38:1423-1435. [PMID: 31506747 DOI: 10.1007/s00345-019-02933-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Accepted: 08/28/2019] [Indexed: 01/07/2023] Open
Abstract
OBJECTIVES The benign prostatic syndrome, comprising lower urinary tract symptomatology secondary to benign prostatic hyperplasia/enlargement, represents a major health care issue in westernized countries. The pharmacological management involves alpha-adrenoceptor antagonists, intervention into the hormonal control of prostate growth using inhibitors of the enzyme 5-alpha-reductase, and stimulation of the nitric oxide/cyclic GMP pathway by tadalafil, an inhibitor of the phosphodiesterase type 5. METHODS This review summarizes the achievements which have been made in the development of drug candidates assumed to offer opportunities as beneficial treatment options in the management of the benign prostatic syndrome. RESULTS A review of the literature has revealed that the line of development is focusing on drugs interfering with peripheral neuromuscular/neuronal mechanisms (nitric oxide donor drugs, agonists/antagonists of endogenous peptides, botulinum toxin, NX-1207), the steroidal axis (cetrorelix) or the metabolic turn-over (lonidamine), as well as the combination of drugs already established in the treatment of lower urinary tract symptomatology/benign prostatic hyperplasia (phosphodiesterase 5 inhibitor plus alpha-adrenoceptor antagonist). CONCLUSION Many research efforts have provided the basis for the development of new therapeutic modalities for the management of lower urinary tract dysfunctions, some of which might be offered to the patients in the near future.
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Affiliation(s)
- Stefan Ückert
- Division of Surgery, Department of Urology and Urological Oncology, Hannover Medical School, 30623, Hannover, Germany.
| | - George T Kedia
- Division of Surgery, Department of Urology and Urological Oncology, Hannover Medical School, 30623, Hannover, Germany
| | - Dimitrios Tsikas
- Core Unit Proteomics, Center of Pharmacology and Toxicology, Hannover Medical School, Hannover, Germany
| | - Annika Simon
- Department of Internal Medicine, Hannover Medical School, Hannover, Germany
| | | | - Markus A Kuczyk
- Division of Surgery, Department of Urology and Urological Oncology, Hannover Medical School, 30623, Hannover, Germany
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Liquid chromatography–mass spectrometry identification of serum biomarkers for nocturia in aged men. World J Urol 2019; 37:2199-2205. [DOI: 10.1007/s00345-019-02647-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Accepted: 01/16/2019] [Indexed: 02/07/2023] Open
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Grundy L, Caldwell A, Brierley SM. Mechanisms Underlying Overactive Bladder and Interstitial Cystitis/Painful Bladder Syndrome. Front Neurosci 2018; 12:931. [PMID: 30618560 PMCID: PMC6299241 DOI: 10.3389/fnins.2018.00931] [Citation(s) in RCA: 86] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Accepted: 11/27/2018] [Indexed: 12/18/2022] Open
Abstract
The bladder is innervated by extrinsic afferents that project into the dorsal horn of the spinal cord, providing sensory input to the micturition centers within the central nervous system. Under normal conditions, the continuous activation of these neurons during bladder distension goes mostly unnoticed. However, for patients with chronic urological disorders such as overactive bladder syndrome (OAB) and interstitial cystitis/painful bladder syndrome (IC/PBS), exaggerated bladder sensation and altered bladder function are common debilitating symptoms. Whilst considered to be separate pathological entities, there is now significant clinical and pre-clinical evidence that both OAB and IC/PBS are related to structural, synaptic, or intrinsic changes in the complex signaling pathways that mediate bladder sensation. This review discusses how urothelial dysfunction, bladder permeability, inflammation, and cross-organ sensitisation between visceral organs can regulate this neuroplasticity. Furthermore, we discuss how the emotional affective component of pain processing, involving dysregulation of the HPA axis and maladaptation to stress, anxiety and depression, can exacerbate aberrant bladder sensation and urological dysfunction. This review reveals the complex nature of urological disorders, highlighting numerous interconnected mechanisms in their pathogenesis. To find appropriate therapeutic treatments for these disorders, it is first essential to understand the mechanisms responsible, incorporating research from every level of the sensory pathway, from bladder to brain.
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Affiliation(s)
- Luke Grundy
- Visceral Pain Research Group, Centre for Neuroscience, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia
- Centre for Nutrition and Gastrointestinal Diseases, Discipline of Medicine, South Australian Health and Medical Research Institute, The University of Adelaide, Adelaide, SA, Australia
| | - Ashlee Caldwell
- Visceral Pain Research Group, Centre for Neuroscience, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia
- Centre for Nutrition and Gastrointestinal Diseases, Discipline of Medicine, South Australian Health and Medical Research Institute, The University of Adelaide, Adelaide, SA, Australia
| | - Stuart M. Brierley
- Visceral Pain Research Group, Centre for Neuroscience, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia
- Centre for Nutrition and Gastrointestinal Diseases, Discipline of Medicine, South Australian Health and Medical Research Institute, The University of Adelaide, Adelaide, SA, Australia
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Abstract
PURPOSE OF REVIEW Multiple sclerosis (MS) is the most frequent neuroinflammatory disease of the central nervous system and is commonly associated with lower urinary tract (LUT) dysfunction. As a consequence, health-related quality of life is often impaired and the upper urinary tract might be at risk for damage. The aim of this review is to give an overview of current treatment options for LUT dysfunction in patients with MS. RECENT FINDINGS The treatment is tailored to the type of dysfunction-storage or voiding dysfunction-beginning with conservative treatment options and ending with invasive therapies and surgery. Additionally, alternative options, e.g., different intravesical therapies or cannabinoids, have been evaluated in recent years with promising results. Current available therapies offer different possible treatments for LUT dysfunction in patients with MS. They address either voiding or storage dysfunction and therefore ameliorate LUT symptoms improve quality of life and protect the upper urinary tract.
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Affiliation(s)
- Jure Tornic
- Department of Uro-Neurology, The National Hospital For Neurology and Neurosurgery and UCL Institute for Neurology, Queen Square, London, WC1N 3BG, UK.
| | - Jalesh N Panicker
- Department of Uro-Neurology, The National Hospital For Neurology and Neurosurgery and UCL Institute for Neurology, Queen Square, London, WC1N 3BG, UK
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Bjorling DE, Wang ZY. Potential of Endocannabinoids to Control Bladder Pain. Front Syst Neurosci 2018; 12:17. [PMID: 29867382 PMCID: PMC5962905 DOI: 10.3389/fnsys.2018.00017] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2017] [Accepted: 04/24/2018] [Indexed: 12/21/2022] Open
Abstract
Bladder-related pain is one of the most common forms of visceral pain, and visceral pain is among the most common complaints for which patients seek physician consultation. Despite extensive studies of visceral innervation and treatment of visceral pain, opioids remain a mainstay for management of bladder pain. Side effects associated with opioid therapy can profoundly diminish quality of life, and improved options for treatment of bladder pain remain a high priority. Endocannabinoids, primarily anandamide (AEA) and 2-arachidonoylglycerol (2-AG), are endogenously-produced fatty acid ethanolamides with that induce analgesia. Animal experiments have demonstrated that inhibition of enzymes that degrade AEA or 2-AG have the potential to prevent development of visceral and somatic pain. Although experimental results in animal models have been promising, clinical application of this approach has proven difficult. In addition to fatty acid amide hydrolase (FAAH; degrades AEA) and monacylglycerol lipase (MAGL; degrades 2-AG), cyclooxygenase (COX) acts to metabolize endocannabinoids. Another potential limitation of this strategy is that AEA activates pro-nociceptive transient receptor potential vanilloid 1 (TRPV1) channels. Dual inhibitors of FAAH and TRPV1 or FAAH and COX have been synthesized and are currently undergoing preclinical testing for efficacy in providing analgesia. Local inhibition of FAAH or MAGL within the bladder may be viable options to reduce pain associated with cystitis with fewer systemic side effects, but this has not been explored. Further investigation is required before manipulation of the endocannabinoid system can be proven as an efficacious alternative for management of bladder pain.
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Affiliation(s)
- Dale E Bjorling
- School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, United States
| | - Zun-Yi Wang
- School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, United States
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Kim SD, Cho KJ, Kim JC. Expression of cannabinoid 1 and, 2 receptors and the effects of cannabinoid 1 and, 2 receptor agonists on detrusor overactivity associated with bladder outlet obstruction in rats. BMC Urol 2017; 17:121. [PMID: 29284441 PMCID: PMC5747270 DOI: 10.1186/s12894-017-0313-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2017] [Accepted: 12/20/2017] [Indexed: 12/21/2022] Open
Abstract
Background This study investigated changes in the expression of cannabinoid (CB) receptors and the effects of CB1 and CB2 agonists on detrusor overactivity (DO) associated with bladder outlet obstruction (BOO) in rats. Methods Male Sprague Dawley rats were randomly assigned to four groups (n = 10) in each group. The control group comprised sham-operated rats. A animals in the BOO, CB1 agonist and CB2 agonist groups all underwent BOO surgery. Three weeks postoperatively, cystometrography (CMG) was performed on all rats. After confirming the presence of DO in the CB1 and CB2 agonist groups, a CB1 agonist (WIN 55,212–2) and a CB2 agonist (CB65) were instilled intravesically, and CMG was repeated. CMG parameters, including the contraction interval (CI) and contraction pressure (CP) were then analyzed. The bladders of rats in all four groups were excised following CMG. Immunofluorescence staining and Western blotting were performed to localize CB1 and CB2 and measure their expression levels in the urothelium and detrusor muscle. Results The CI was significantly longer and the CP was significantly lower in the CB1 agonist group than in the BOO group. CI and CP in the CB2 agonist group showed the same results. CB1 receptor immunofluorescence staining signals and immunoreactive bands in Western blotting were increased in the BOO group compared with results in the control group. Similarly, results for the CB2 receptor were also increased in the BOO group, although this difference was not significant. The CMG parameters in the BOO group were significantly improved by the inhibitory effects of CB1 and CB2 agonists on BOO-associated DO. The expression of CB1 was significantly increased in the urothelium and detrusor muscle in BOO-associated DO, but no significant change in CB2 expression was observed. Conclusions CB1 and CB2 receptors, especially CB1, play a role in the pathophysiology of BOO-associated DO, and could serve as therapeutic targets.
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Affiliation(s)
- Sung Dae Kim
- Department of Urology, Graduate School of Medicine, Jeju National University, Jeju, South Korea
| | - Kang Jun Cho
- Department of Urology, Bucheon St. Mary's hospital, College of Medicine, The Catholic University of Korea, Sosa-Ro 327, Wonmi-gu, Bucheon-si, Gyeonggi-do, Seoul, 14647, South Korea
| | - Joon Chul Kim
- Department of Urology, Bucheon St. Mary's hospital, College of Medicine, The Catholic University of Korea, Sosa-Ro 327, Wonmi-gu, Bucheon-si, Gyeonggi-do, Seoul, 14647, South Korea.
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THC/CBD oromucosal spray in patients with multiple sclerosis overactive bladder: a pilot prospective study. Neurol Sci 2017; 39:97-102. [PMID: 29052091 DOI: 10.1007/s10072-017-3148-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Accepted: 10/06/2017] [Indexed: 12/20/2022]
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Ückert S, la Croce G, Bettiga A, Albrecht K, Buono R, Benigni F, Kuczyk MA, Hedlund P. Expression and distribution of key proteins of the endocannabinoid system in the human seminal vesicles. Andrologia 2017; 50. [PMID: 28786134 DOI: 10.1111/and.12875] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/01/2017] [Indexed: 12/25/2022] Open
Abstract
The endocannabinoid system (ECS), comprising the cannabinoid receptors (CBR), their ligands, and enzymes controlling the turnover of endocannabinoids, has been suggested to be involved in male reproductive function. As information is scarce on the expression of the ECS in human male reproductive tissues, this study aimed to investigate by means of molecular biology (RT-PCR) and immunohistochemistry/immunofluorescence the expression and distribution of CB1 and CB2, GPR55 (an orphan G protein-coupled receptor that recognises cannabinoid ligands) and FAAH (isoforms 1 and 2) in the human seminal vesicles (SV). The specimens expressed PCR products corresponding to CB1 (66 bp), CB2 (141 bp), GPR55 (112 bp), FAAH1 (260 bp) and FAAH2 (387 bp). Immumohistochemistry revealed dense expression of CB1, CB2 and GPR55 located to the pseudo-stratified columnar epithelium and varicose nerves (also characterised by the expression of vasoactive intestinal polypeptide and calcitonin gene-related peptide). Cytosolic staining for FAAH1 and FAAH2 was seen in cuboidal cells of all layers of the epithelium. No immunoreactivity was detected in the smooth musculature or nerve fibres. CB1, CB2, GPR55, FAAH1 and FAAH2 are highly expressed in the human SV. Considering their localisation, the ECS may be involved in epithelial homeostasis, secretory function or autonomic mechano-afferent signalling.
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Affiliation(s)
- S Ückert
- Division of Surgery, Department of Urology & Urological Oncology, Hannover Medical School, Hannover, Germany
| | - G la Croce
- Faculty of Medicine, Urological Research Institute (URI), University Vita Salute San Raffaele, Milano, Italy
| | - A Bettiga
- Faculty of Medicine, Urological Research Institute (URI), University Vita Salute San Raffaele, Milano, Italy
| | - K Albrecht
- Institute for Legal (Forensic) Medicine, Hannover Medical School, Hannover, Germany
| | - R Buono
- Department of Gerontology, University of Southern California (USC), Los Angeles, CA, USA
| | - F Benigni
- Faculty of Medicine, Urological Research Institute (URI), University Vita Salute San Raffaele, Milano, Italy
| | - M A Kuczyk
- Division of Surgery, Department of Urology & Urological Oncology, Hannover Medical School, Hannover, Germany
| | - P Hedlund
- Department of Clinical Pharmacology, Faculty of Medicine, Lund University, Lund, Sweden
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Abo Youssef N, Schneider MP, Mordasini L, Ineichen BV, Bachmann LM, Chartier-Kastler E, Panicker JN, Kessler TM. Cannabinoids for treating neurogenic lower urinary tract dysfunction in patients with multiple sclerosis: a systematic review and meta-analysis. BJU Int 2017; 119:515-521. [DOI: 10.1111/bju.13759] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
- Nadim Abo Youssef
- Neuro-Urology, Spinal Cord Injury Center and Research; Balgrist University Hospital; University of Zürich; Zürich Switzerland
| | - Marc P. Schneider
- Neuro-Urology, Spinal Cord Injury Center and Research; Balgrist University Hospital; University of Zürich; Zürich Switzerland
- Brain Research Institute; University of Zürich; Zürich Switzerland
- Department of Health Sciences and Technology; Swiss Federal Institute of Technology Zürich; Zürich Switzerland
| | - Livio Mordasini
- Department of Urology; Cantonal Hospital Lucerne; Lucerne Switzerland
| | - Benjamin V. Ineichen
- Brain Research Institute; University of Zürich; Zürich Switzerland
- Department of Health Sciences and Technology; Swiss Federal Institute of Technology Zürich; Zürich Switzerland
| | | | - Emmanuel Chartier-Kastler
- Department of Urology; Academic Hospital Pitié-Salpêtrière; Assistance Publique-Hôpitaux de Paris; Pierre et Marie Curie Medical School; Sorbonne Universités; Paris 6 University; Paris France
| | - Jalesh N. Panicker
- Department of Uro-Neurology; National Hospital for Neurology and Neurosurgery and UCL Institute of Neurology; London UK
| | - Thomas M. Kessler
- Neuro-Urology, Spinal Cord Injury Center and Research; Balgrist University Hospital; University of Zürich; Zürich Switzerland
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Abstract
PURPOSE OF REVIEW This review aims to analyze and discuss all recently published articles associated with neurogenic voiding discussion providing readers with the most updated knowledge and trigger for further research. RECENT FINDINGS They include the proposal of a novel classification system for the pathophysiology of neurogenic lower urinary tract dysfunction (NLUTD) which combines neurological defect in a distinct anatomic location, and data on bowel dysfunction, autonomic dysreflexia and urine biomarkers; review of patient-reported outcome measures in NLUTD; review of the criteria for the diagnosis of clinically significant urinary infections; novel research findings on the pathophysiology of NLUTD; and review of data on minimally and more invasive treatments. SUMMARY Despite the extended evidence base on NLUTD, there is a paucity of high-quality new research concerning voiding dysfunction as opposed to storage problems. The update aims to inform clinicians about new developments in clinical practice, as well as ignite discussion for further clinical and basic research in the aforementioned areas of NLUTD.
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Munoz A. Unmasking roles of the peripheral endocannabinoid system associated with bladder overactivity. BJU Int 2016; 117:713-4. [PMID: 27079478 DOI: 10.1111/bju.13336] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Affiliation(s)
- Alvaro Munoz
- Departments of Regenerative Medicine and Urology, Houston Methodist Research Institute and Houston Methodist Hospital, Houston, TX, USA
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Hedlund P, Gratzke C. The endocannabinoid system — a target for the treatment of LUTS? Nat Rev Urol 2016; 13:463-70. [DOI: 10.1038/nrurol.2016.110] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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Blaha I, Recio P, Martínez MP, López-Oliva ME, Ribeiro ASF, Agis-Torres Á, Martínez AC, Benedito S, García-Sacristán A, Fernandes VS, Hernández M. Impaired Excitatory Neurotransmission in the Urinary Bladder from the Obese Zucker Rat: Role of Cannabinoid Receptors. PLoS One 2016; 11:e0157424. [PMID: 27285468 PMCID: PMC4902197 DOI: 10.1371/journal.pone.0157424] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2016] [Accepted: 05/31/2016] [Indexed: 11/19/2022] Open
Abstract
Metabolic syndrome (MS) is a known risk factor for lower urinary tract symptoms. This study investigates whether functional and expression changes of cannabinoid CB1 and CB2 receptors are involved in the bladder dysfunction in an obese rat model with insulin resistance. Bladder samples from obese Zucker rat (OZR) and their respective controls lean Zucker rat (LZR) were processed for immunohistochemistry and western blot for studying the cannabinoid receptors expression. Detrusor smooth muscle (DSM) strips from LZR and OZR were also mounted in myographs for isometric force recordings. Neuronal and smooth muscle CB1 and CB2 receptor expression and the nerve fiber density was diminished in the OZR bladder. Electrical field stimulation (EFS) and acetylcholine (ACh) induced frequency- and concentration-dependent contractions of LZR and OZR DSM. ACh contractile responses were similar in LZR and OZR. EFS-elicited contractions, however, were reduced in OZR bladder. Cannabinoid receptor agonists and antagonists failed to modify the DSM basal tension in LZR and OZR In LZR bladder, EFS responses were inhibited by ACEA and SER-601, CB1 and CB2 receptor agonists, respectively, these effects being reversed by ACEA plus the CB1 antagonist, AM-251 or SER-601 plus the CB2 antagonist, AM-630. In OZR bladder, the inhibitory action of ACEA on nerve-evoked contractions was diminished, whereas that SER-601 did not change EFS responses. These results suggest that a diminished function and expression of neuronal cannabinoid CB1 and CB2 receptors, as well as a lower nerve fiber density is involved in the impaired excitatory neurotransmission of the urinary bladder from the OZR.
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MESH Headings
- Animals
- Male
- Muscle Contraction
- Muscle, Smooth/innervation
- Muscle, Smooth/pathology
- Muscle, Smooth/physiopathology
- Nerve Fibers/pathology
- Obesity/pathology
- Obesity/physiopathology
- Rats
- Rats, Zucker
- Receptor, Cannabinoid, CB1/analysis
- Receptor, Cannabinoid, CB1/metabolism
- Receptor, Cannabinoid, CB2/analysis
- Receptor, Cannabinoid, CB2/metabolism
- Synaptic Transmission
- Urinary Bladder/innervation
- Urinary Bladder/pathology
- Urinary Bladder/physiopathology
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Affiliation(s)
- Igor Blaha
- Departamento de Urología, Hospital General Universitario Gregorio Marañón, 28007-Madrid
| | - Paz Recio
- Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040-Madrid
| | - María Pilar Martínez
- Departamento de Anatomía y Anatomía Patológica Comparadas, Facultad de Veterinaria, Universidad Complutense de Madrid, 28040-Madrid
| | - María Elvira López-Oliva
- Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040-Madrid
| | - Ana S. F. Ribeiro
- Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040-Madrid
| | - Ángel Agis-Torres
- Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040-Madrid
| | - Ana Cristina Martínez
- Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040-Madrid
| | - Sara Benedito
- Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040-Madrid
| | - Albino García-Sacristán
- Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040-Madrid
| | - Vítor S. Fernandes
- Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040-Madrid
| | - Medardo Hernández
- Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040-Madrid
- * E-mail:
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Anandamide transporter-mediated regulation of the micturition reflex in urethane-anesthetized rats. Int Urol Nephrol 2016; 48:1407-12. [PMID: 27256398 DOI: 10.1007/s11255-016-1329-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2016] [Accepted: 05/21/2016] [Indexed: 10/21/2022]
Abstract
PURPOSE The aim of this study was to investigate the effects of an anandamide transporter inhibitor that can increase endogenous anandamide concentration on the micturition reflex in urethane-anesthetized rats. METHODS Continuous cystometrograms were performed in female Sprague-Dawley rats under urethane anesthesia. After stable micturition cycles were established, VDM11 (1, 3 and 10 mg/kg), an anandamide membrane transporter inhibitor, was administered intravenously to evaluate changes in bladder activity. In experiments examining the effects of cannabinoid (CB) receptor antagonists, VDM11 (10 mg/kg) was injected intravenously when the first bladder contraction was observed after intravenous administration of AM251, a CB1 receptor antagonist (3 mg/kg), or AM630, a CB2 receptor antagonist (3 mg/kg). RESULTS Intravenous administration of VDM11 increased intercontraction intervals and threshold pressure at doses of 3 mg/kg or higher in dose-dependent fashion. When AM251 was administered one voiding cycle before VDM11 administration, the increases in intercontraction intervals and threshold pressure induced by VDM11 administration alone were not seen. In contrast, when AM630 was administered before VDM11 administration, increases in intercontraction intervals and threshold pressure were observed, as they were after VDM11 alone. CONCLUSION These results suggest that anandamide, an endogenous CB ligand, can modulate the micturition reflex and that anandamide transporters play an important role in this modulation. In urethane-anesthetized rats, inhibition of the uptake of anandamide can inhibit the micturition reflex and these inhibitory effects of VDM11 are at least in part mediated by the CB1 receptor.
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Andersson KE. Potential Future Pharmacological Treatment of Bladder Dysfunction. Basic Clin Pharmacol Toxicol 2016; 119 Suppl 3:75-85. [DOI: 10.1111/bcpt.12577] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2015] [Accepted: 12/23/2016] [Indexed: 12/16/2022]
Affiliation(s)
- Karl-Erik Andersson
- Institute for Regenerative Medicine; Wake Forest University School of Medicine; Winston Salem NC USA
- Aarhus Institute for Advanced Sciences (AIAS); Aarhus University; Aarhus Denmark
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Cannabinoids to treat spinal cord injury. Prog Neuropsychopharmacol Biol Psychiatry 2016; 64:190-9. [PMID: 25805333 DOI: 10.1016/j.pnpbp.2015.03.008] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2015] [Revised: 03/09/2015] [Accepted: 03/13/2015] [Indexed: 02/06/2023]
Abstract
Spinal cord injury (SCI) is a devastating condition for which there is no standard treatment beyond rehabilitation strategies. In this review, we discuss the current knowledge on the use of cannabinoids to treat this condition. The endocannabinoid system is expressed in the intact spinal cord, and it is dramatically upregulated after lesion. Endogenous activation of this system counteracts secondary damage following SCI, and treatments with endocannabinoids or synthetic cannabinoid receptor agonists promote a better functional outcome in experimental models. The use of cannabinoids in SCI is a new research field and many questions remain open. Here, we discuss caveats and suggest some future directions that may help to understand the role of cannabinoids in SCI and how to take advantage of this system to regain functions after spinal cord damage.
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Andersson KE. Drug therapy of overactive bladder--what is coming next? Korean J Urol 2015; 56:673-9. [PMID: 26495067 PMCID: PMC4610893 DOI: 10.4111/kju.2015.56.10.673] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2015] [Accepted: 09/03/2015] [Indexed: 01/25/2023] Open
Abstract
After the approval and introduction of mirabegron, tadalafil, and botulinum toxin A for treatment of lower urinary tract symptoms/overactive bladder, focus of interest has been on their place in therapy versus the previous gold standard, antimuscarinics. However, since these agents also have limitations there has been increasing interest in what is coming next - what is in the pipeline? Despite progress in our knowledge of different factors involved in both peripheral and central modulation of lower urinary tract dysfunction, there are few innovations in the pipe-line. Most developments concern modifications of existing principles (antimuscarinics, β3-receptor agonists, botulinum toxin A). However, there are several new and old targets/drugs of potential interest for further development, such as the purinergic and cannabinoid systems and the different members of the transient receptor potential channel family. However, even if there seems to be good rationale for further development of these principles, further exploration of their involvement in lower urinary tract function/dysfunction is necessary.
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Affiliation(s)
- Karl-Erik Andersson
- Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston Salem, NC, USA. ; Aarhus Institute for Advanced Sciences, Aarhus University, Aarhus, Denmark
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Aizawa N, Gandaglia G, Hedlund P, Fujimura T, Fukuhara H, Montorsi F, Homma Y, Igawa Y. 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 2015; 117:821-8. [PMID: 26189783 DOI: 10.1111/bju.13223] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
OBJECTIVE To determine if inhibition of the endocannabinoid-degrading enzyme fatty acid amide hydrolase (FAAH) can counteract the changes in urodynamic variables and bladder afferent activities induced by intravesical prostaglandin E2 (PGE2 ) instillation in rats. MATERIALS AND METHODS In female Sprague-Dawley rats we studied the effects of URB937, a peripherally restricted FAAH inhibitor, on single-unit afferent activity (SAA) during PGE2 -induced bladder overactivity (BO). SAA measurements were made in urethane-anaesthetised rats and Aδ- and C-fibres were identified by electrical stimulation of the pelvic nerve and by bladder distention. Cystometry (CMG) in conscious animals and during SAA measurements was performed during intravesical instillation of PGE2 (50 or 100 μm) after intravenous administration of URB937 (0.1 and 1 mg/kg) or vehicle. In separate experiments, the comparative expressions of FAAH and cannabinoid receptors, CB1 and CB2 , in microsurgically removed L6 dorsal root ganglion (DRG) were studied by immunofluorescence. RESULTS During CMG, 1 mg/kg URB937, but not vehicle or 0.1 mg/kg URB937, counteracted the PGE2 -induced changes in urodynamic variables. PGE2 increased the SAAs of C-fibres, but not Aδ-fibres. URB937 (1 mg/kg) depressed Aδ-fibre SAA and abolished the facilitated C-fibre SAA induced by PGE2 . The DRG nerve cells showed strong staining for FAAH, CB1 and CB2 , with a mean (sem) of 77 (2)% and 87 (3)% of FAAH-positive nerve cell bodies co-expressing CB1 or CB2 immunofluorescence, respectively. CONCLUSION The present results show that URB937, a peripherally restricted FAAH inhibitor, reduces BO and C-fibre hyperactivity in the rat bladder provoked by PGE2 , suggesting an important role of the peripheral endocannabinoid system in BO and hypersensitivity.
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Affiliation(s)
- Naoki Aizawa
- Department of Continence Medicine, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Giorgio Gandaglia
- Division of Oncology/Unit of Urology, Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy.,Department of Clinical and Experimental Pharmacology, Lund University, Lund, Sweden
| | - Petter Hedlund
- Division of Drug Research, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden
| | - Tetsuya Fujimura
- Department of Urology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Hiroshi Fukuhara
- Department of Urology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Francesco Montorsi
- Division of Oncology/Unit of Urology, Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Yukio Homma
- Department of Urology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Yasuhiko Igawa
- Department of Continence Medicine, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
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Juszczak K, Maciukiewicz P. The role of the peripheral cannabinoid system in the pathogenesis of detrusor overactivity evoked by increased intravesical osmolarity in rats. Can J Physiol Pharmacol 2015; 93:721-6. [DOI: 10.1139/cjpp-2015-0091] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The cannabinoid receptors CB1 and CB2 are localized in the urinary bladder and play a role in the regulation of its function. We investigated the pathomechanisms through which hyperosmolarity induces detrusor overactivity (DO). We compared urinary bladder activity in response to blockade of CB1 and CB2 receptors using AM281 and AM630, respectively, in normal rats and after hyperosmolar stimulation. Experiments were performed on 44 rats. DO was induced by intravesical instillation of hyperosmolar saline. Surgical procedures and cystometry were performed under urethane anaesthesia. The measurements represent the average of 5 bladder micturition cycles. We analysed basal, threshold, and micturition voiding pressure; intercontraction interval; compliance; functional bladder capacity; motility index; and detrusor overactivity index. The blockage of CB1 and CB2 receptors diminished the severity of hyperosmolar-induced DO. In comparison with naïve animals the increased frequency of voiding with no significant effect on intravesical voiding pressure profile was observed as a result of the blockage of CB1 and CB2 receptors. These results demonstrate that hyperosmolar-induced DO is mediated by CB1 and CB2 receptors. Therefore, the cannabinoid pathway could potentially be a target for the treatment of urinary bladder dysfunction.
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Affiliation(s)
- Kajetan Juszczak
- Department of Urology, Ludwik Rydygier Memorial Hospital, Złotej Jesieni 1, 31-826 Cracow, Poland
- Department of Pathophysiology, Jagiellonian University, Medical College, Cracow, Poland
| | - Piotr Maciukiewicz
- Department of Urology, Ludwik Rydygier Memorial Hospital, Złotej Jesieni 1, 31-826 Cracow, Poland
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Bakali E, McDonald J, Elliott RA, Lambert DG, Tincello DG. Cannabinoid receptor expression in the bladder is altered in detrusor overactivity. Int Urogynecol J 2015. [PMID: 26224382 DOI: 10.1007/s00192-015-2802-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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 [(3)H]-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.
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Affiliation(s)
- Evangelia Bakali
- Reproductive Sciences Section, Health Sciences, University of Leicester, Leicester, UK. .,Department of Health Sciences, Leicester Royal Infirmary, University of Leicester, Robert Kilpatrick Clinical Sciences Building, Leicester, LE2 7LX, UK.
| | - John McDonald
- Department of Cardiovascular Sciences, University of Leicester, Leicester, UK
| | - Ruth A Elliott
- Reproductive Sciences Section, Health Sciences, University of Leicester, Leicester, UK
| | - David G Lambert
- Department of Cardiovascular Sciences, University of Leicester, Leicester, UK
| | - Douglas G Tincello
- Reproductive Sciences Section, Health Sciences, University of Leicester, Leicester, UK
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Differential Response to Medical Therapy for Male Lower Urinary Tract Symptoms. CURRENT BLADDER DYSFUNCTION REPORTS 2015. [DOI: 10.1007/s11884-015-0295-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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Pagano E, Montanaro V, di Girolamo A, Pistone A, Altieri V, Zjawiony JK, Izzo AA, Capasso R. Effect of Non-psychotropic Plant-derived Cannabinoids on Bladder Contractility: Focus on Cannabigerol. Nat Prod Commun 2015. [DOI: 10.1177/1934578x1501000653] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
There are anecdotal reports that some Cannabis preparations may be useful for bladder dysfunctions. Here, we investigated the effect of a number of non-psychotropic phytocannabinoids, namely cannabidiol (CBD), cannabigerol (CBG), cannabidivarin (CBDV), Δ9-tetrahydrocannabivarin (THCV) and cannabichromene (CBC) on mouse bladder contractility in vitro. CBG, THCV, CBD and CBDV, but not CBC, at concentration ranging from 10−8M to 10−4M, decreased (with similar potency), the contractions induced by acetylcholine without significantly modifying the contractions induced by electrical stimulation. The rank order of efficacy was CBG=THCV>CBD>CBDV. In depth studies on CBG showed that the effect of this phytocannabinoid on acetylcholine-induced contractions was not affected by CB1or CB2receptor antagonists. Additionally, CBG also reduced acetylcholine-induced contractions in the human bladder.
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Affiliation(s)
- Ester Pagano
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
- Endocannabinoid Research Group, University of Salerno, Salerno, Italy
| | - Vittorino Montanaro
- Department of Kidney Transplantation, University of Naples Federico II, Naples, Italy
| | | | - Antonio Pistone
- Department of Urology, University of Naples Federico II, Naples, Italy
| | | | - Jordan K. Zjawiony
- Department of BioMolecular Sciences, Division of Pharmacognosy, School of Pharmacy, University of Mississippi, P.O. Box 1848, University, MS 38677, USA
| | - Angelo A. Izzo
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
- Endocannabinoid Research Group, University of Salerno, Salerno, Italy
| | - Raffaele Capasso
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
- Endocannabinoid Research Group, University of Salerno, Salerno, Italy
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Sacco E, Recupero S, Bientinesi R, Palermo G, D’Agostino D, Currò D, Bassi P. Pioneering drugs for overactive bladder and detrusor overactivity: Ongoing research and future directions. World J Obstet Gynecol 2015; 4:24-39. [DOI: 10.5317/wjog.v4.i2.24] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2014] [Revised: 01/31/2015] [Accepted: 04/14/2015] [Indexed: 02/05/2023] Open
Abstract
The ongoing research on pioneering drug candidates for the overactive bladder (OAB) aimed to overcome the limitations of currently licensed pharmacotherapies, such as antimuscarinics, β3-adrenergic agents, and botulinum neurotoxin, has been reviewed performing a systematic literature review and web search. The review covers the exploratory agents alternative to available medications for OAB and that may ultimately prove to be therapeutically useful in the future management of OAB patients based on preclinical and early clinical data. It emerges that many alternative pharmacological strategies have been discovered or are under investigation in disease-oriented studies. Several potential therapeutics are known for years but still find obstacles to pass the clinical stages of development, while other completely novel compounds, targeting new pharmacological targets, have been recently discovered and show potential to translate into clinical therapeutic agents for idiopathic and neurogenic OAB syndrome. The global scenario of investigational drugs for OAB gives promise for the development of innovative therapeutics that may ultimately prove effective as first, combined or second-line treatments within a realistic timescale of ten years.
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Patra PB, Patra S. Research Findings on Overactive Bladder. Curr Urol 2015; 8:1-21. [PMID: 26195957 PMCID: PMC4483299 DOI: 10.1159/000365682] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2013] [Accepted: 01/09/2014] [Indexed: 12/19/2022] Open
Abstract
Several physiopathologic conditions lead to the manifestation of overactive bladder (OAB). These conditions include ageing, diabetes mellitus, bladder outlet obstruction, spinal cord injury, stroke and brain injury, Parkinson's disease, multiple sclerosis, interstitial cystitis, stress and depression. This review has discussed research findings in human and animal studies conducted on the above conditions. Several structural and functional changes under these conditions have not only been observed in the lower urinary tract, but also in the brain and spinal cord. Significant changes were observed in the following areas: neurotransmitters, prostaglandins, nerve growth factor, Rho-kinase, interstitial cells of Cajal, and ion and transient receptor potential channels. Interestingly, alterations in these areas showed great variation in each of the conditions of the OAB, suggesting that the pathophysiology of the OAB might be different in each condition of the disease. It is anticipated that this review will be helpful for further research on new and specific drug development against OAB.
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Affiliation(s)
- Phani B. Patra
- King of Prussia, Drexel University College of Medicine, Philadelphia, Pa., USA
| | - Sayani Patra
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pa., USA
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Füllhase C, Schreiber A, Giese A, Schmidt M, Montorsi F, Gratzke C, La Croce G, Castiglione F, Stief C, Hedlund P. Spinal neuronal cannabinoid receptors mediate urodynamic effects of systemic fatty acid amide hydrolase (FAAH) inhibition in rats. Neurourol Urodyn 2015; 35:464-70. [PMID: 25788026 DOI: 10.1002/nau.22753] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2014] [Accepted: 01/21/2015] [Indexed: 01/28/2023]
Abstract
AIMS To test if urodynamic effects from systemic Fatty Acid Amide Hydrolase (FAAH) inhibition involve sacral spinal cannabinoid type 1 (CB1) or type 2 (CB2) receptors. METHODS Male rats with or without partial urethral obstruction were used for cystometry or immunohistochemistry. Urodynamic effects of intravenous (IV) 0.3 mg/kg Oleoyl Ethyl Amide (OEtA; FAAH inhibitor), and intrathecal (IT) 5 μg rimonabant (CB1 antagonist) or 5 μg SR144528 (CB2 antagonist) were studied in awake rats. RESULTS After administration of rimonabant or SR144528, non-obstructed rats with normal bladder function developed bladder overactivity (BO), which was counteracted by OEtA. OEtA also counteracted BO in obstructed rats. SR144528 did not affect bladder function in obstructed rats but counteracted the urodynamic effects of OEtA. Surprisingly, rimonabant (and AM251, another CB1 antagonist) reduced BO in obstructed rats, whereafter OEtA produced no additional urodynamic effects. CB1 expression increased in the sacral spinal cord of obstructed rats whereas no changes were observed for CB2 or FAAH. CONCLUSIONS Urodynamic effects of systemic FAAH inhibition involve activities at spinal neuronal CB1 and CB2 receptors in normal and obstructed rats. Endogenous spinal CB receptor ligands seem to regulate normal micturition and BO. Altered spinal CB receptor functions may be involved in the pathogenesis of obstruction-induced BO. Neurourol. Urodynam. 35:464-470, 2016. © 2015 Wiley Periodicals, Inc.
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Affiliation(s)
- Claudius Füllhase
- Department of Urology, University of Rostock, Rostock, Germany.,Walter Brendel Centre of Experimental Medicine, Ludwig-Maximilians-University, Munich, Germany
| | - Andrea Schreiber
- Walter Brendel Centre of Experimental Medicine, Ludwig-Maximilians-University, Munich, Germany.,Department of Urology, Ludwig-Maximilians-University, Munich, Germany
| | - Armin Giese
- Center for Neuropathology and Prion Research, Ludwig-Maximilians-University, Munich, Germany
| | - Michael Schmidt
- Department of Urology, Ludwig-Maximilians-University, Munich, Germany
| | - Francesco Montorsi
- Division of Oncology/Unit of Urology, Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy.,Universita Vita San Raffaele, Milan, Italy
| | - Christian Gratzke
- Department of Urology, Ludwig-Maximilians-University, Munich, Germany
| | - Giovanni La Croce
- Division of Oncology/Unit of Urology, Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy.,Department of Clinical and Experimental Pharmacology, Lund University, Lund, Sweden
| | - Fabio Castiglione
- Universita Vita San Raffaele, Milan, Italy.,Department of Clinical and Experimental Pharmacology, Lund University, Lund, Sweden
| | - Christian Stief
- Department of Urology, Ludwig-Maximilians-University, Munich, Germany
| | - Petter Hedlund
- Division of Oncology/Unit of Urology, Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy.,Department of Clinical Pharmacology, Linköping University, Linköping, Sweden
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Wang ZY, Wang P, Bjorling DE. Activation of cannabinoid receptor 1 inhibits increased bladder activity induced by nerve growth factor. Neurosci Lett 2015; 589:19-24. [PMID: 25575795 DOI: 10.1016/j.neulet.2015.01.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2014] [Revised: 12/19/2014] [Accepted: 01/03/2015] [Indexed: 12/27/2022]
Abstract
Nerve growth factor (NGF) is an important mediator of inflammatory pain, in part by sensitizing afferent nerve fibers, and expression of NGF is increased during bladder inflammation. We investigated whether intravesical instillation of the selective cannabinoid receptor 1 (CB1) agonist arachidonyl-2'-chloroethylamide (ACEA) affects NGF-induced increased bladder activity in female C57BL/6J wild-type (WT) mice. We also examined the effects of intravesical NGF in female fatty acid amide hydrolase knock-out (FAAH KO) mice. We found that CB1 and tyrosine kinase A (trkA, the high-affinity NGF receptor) were present in L6 dorsal root ganglion (DRG) afferent neurons and in bladders of both genotypes. Intravesical NGF increased bladder activity that was inhibited by intravesical ACEA in WT mice. The inhibitory effects of ACEA were reversed by the selective CB1 antagonist AM 251. Intravesical NGF failed to affect bladder activity in FAAH KO mice, and treatment with AM251, restored the stimulatory effects of NGF on the bladder in FAAH KO mice. These results indicate that activation of CB1 inhibits increased bladder activity induced by NGF.
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Affiliation(s)
- Zun-Yi Wang
- Departments of Surgical Sciences, University of Wisconsin, Madison, WI, USA.
| | - Peiqing Wang
- Departments of Surgical Sciences, University of Wisconsin, Madison, WI, USA
| | - Dale E Bjorling
- Departments of Surgical Sciences, University of Wisconsin, Madison, WI, USA; Departments of Urology, University of Wisconsin, Madison, WI, USA.
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Attenuation of cystitis and pain sensation in mice lacking fatty acid amide hydrolase. J Mol Neurosci 2014; 55:968-76. [PMID: 25374388 DOI: 10.1007/s12031-014-0453-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2014] [Accepted: 10/20/2014] [Indexed: 12/21/2022]
Abstract
Endocannabinoids, such as N-arachidonoylethanolamine (AEA, also called anandamide), exert potent analgesic and anti-inflammatory effects. Fatty acid amide hydrolase (FAAH) is primarily responsible for degradation of AEA, and deletion of FAAH increases AEA content in various tissues. Since FAAH has been shown to be present in the bladder of various species, we compared bladder function, severity of experimental cystitis, and cystitis-associated referred hyperalgesia in male wild-type (WT) and FAAH knock-out (KO) mice. Basal concentrations of AEA were greater, and the severity of cyclophosphamide (CYP)-induced cystitis was reduced in bladders from FAAH KO compared to WT mice. Cystitis-associated increased peripheral sensitivity to mechanical stimuli and enhanced bladder activity (as reflected by increased voiding frequency) were attenuated in FAAH KO compared to WT mice. Further, abundances of mRNA for several pro-inflammatory compounds were increased in the bladder mucosa after CYP treatment of WT mice, and this increase was inhibited in FAAH KO mice. These data indicate that endogenous substrates of FAAH, including the cannabinoid AEA, play an inhibitory role in bladder inflammation and subsequent changes in pain perception. Therefore, FAAH could be a therapeutic target to treat clinical symptoms of painful inflammatory bladder diseases.
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Vizzard MA. New modulatory pathways in micturition reflex function. J Urol 2014; 192:638-9. [PMID: 24946218 DOI: 10.1016/j.juro.2014.06.034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/10/2014] [Indexed: 11/18/2022]
Affiliation(s)
- Margaret A Vizzard
- Department of Neurological Sciences, University of Vermont College of Medicine, Burlington, Vermont
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