The role of metabotropic glutamate receptor mGlu5 in control of micturition and bladder nociception

You-min, HU; Dong, Li; Sun, Binbin; Guillon, M.; Burbach, Leah R.; Nunn, Philip A.; Liu, Xingrong; Vilenski, Olga; Ford, Anthony; Zhong, Yu; Rong, Weifang

doi:10.1016/j.neulet.2008.11.026

Cited by 20 publications

(26 citation statements)

References 27 publications

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“…Thus, the intravesical application of metabotropic glutamate receptor antagonists has no effect on bladder contractility and pelvic nerve afferent firing in normal rats. 30 Studies in animal disease models are needed to es tablish the potential involvement of peripheral glutamate/glutamatergic receptors in the bladder.…”

Section: Discussionmentioning

confidence: 99%

Expression of Vesicular Glutamate Transporters in Sensory and Autonomic Neurons Innervating the Mouse Bladder

et al. 2013

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Purpose VGLUTs, which are essential for loading glutamate into synaptic vesicles, are present in various neuronal systems. However, to our knowledge the expression of VGLUTs in neurons innervating the bladder has not yet been analyzed. We studied VGLUT1, VGLUT2 and VGLUT3 in mouse bladder neurons. Materials and Methods We analyzed the expression of VGLUT1, VGLUT2 and calcitonin gene-related peptide by immunohistochemistry in the retrograde labeled primary afferent and autonomic neurons of BALB/c mice after injecting fast blue in the bladder wall. To study VGLUT3 we traced the bladder of transgenic mice, in which VGLUT3 is identified by enhanced green fluorescent protein detection. Results Most bladder dorsal root ganglion neurons expressed VGLUT2. A smaller percentage of neurons also expressed VGLUT1 or VGLUT3. Co-expression with calcitonin gene-related peptide was only observed for VGLUT2. Occasional VGLUT2 immunoreactive neurons were seen in the major pelvic ganglia. Abundant VGLUT2 immunoreactive nerves were detected in the bladder dome and trigone, and the urethra. VGLUT1 immunoreactive nerves were discretely present. Conclusions We present what are to our knowledge novel data on VGLUT expression in sensory and autonomic neurons innervating the mouse bladder. The frequent association of VGLUT2 and calcitonin gene-related peptide in sensory neurons suggests interactions between glutamatergic and peptidergic neurotransmissions, potentially influencing commonly perceived sensations in the bladder, such as discomfort and pain.

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Section: Discussionmentioning

confidence: 99%

Expression of Vesicular Glutamate Transporters in Sensory and Autonomic Neurons Innervating the Mouse Bladder

et al. 2013

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“…Further, the threshold to evoke a visceromotor response to UBD in rats occurs at similar intravesical pressures (20-40 mmHg) that produce discomfort during UBD in healthy female volunteers (24.4 ± 2.4 cm H 2 O; Ness et al 1998Ness et al , 2005. Thus, UBD produces robust, reliable, and reproducible, stimulus-linked visceromotor responses in rat and mouse models that are readily quantifiable Ness and Elhefni 2004;DeBerry et al 2007;Hu et al 2009;Ball et al 2010), reproducible after an initial sensitization period , and attenuated by commonly used analgesics including morphine, fentanyl, and lidocaine . Accordingly, UBD satisfies criteria for a valid model of visceral nociception in nonhuman animals.…”

Section: Urinary Bladder Distensionmentioning

confidence: 98%

Visceral Pain

Schwartz¹,

Gebhart²

2014

Current Topics in Behavioral Neurosciences

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Modeling visceral pain requires an appreciation of the underlying neurobiology of visceral sensation, including characteristics of visceral pain that distinguish it from pain arising from other tissues, the unique sensory innervation of visceral organs, the functional basis of visceral pain, and the concept of viscero-somatic and viscero-visceral convergence. Further, stimuli that are noxious when applied to the viscera are different than stimuli noxious to skin, muscle, and joints, thus informing model development and assessment. Visceral pain remains an important and understudied area of pain research and basic science knowledge and mechanisms acquired using animal models can translate into approaches that can be applied to the study and development of future therapeutics.

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“…Bladder contraction frequency was measured in rats as described previously (Hu et al, 2009). In brief, the urinary bladder was cannulated under anesthesia in rats and infused with saline to evoke micturition contractions.…”

Section: Basimglurant An Mglu5 Nam In Development For Depressionmentioning

confidence: 99%

Pharmacology of Basimglurant (RO4917523, RG7090), a Unique Metabotropic Glutamate Receptor 5 Negative Allosteric Modulator in Clinical Development for Depression

Lindemann

Porter

Scharf

et al. 2015

J Pharmacol Exp Ther

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Major depressive disorder (MDD) is a serious public health burden and a leading cause of disability. Its pharmacotherapy is currently limited to modulators of monoamine neurotransmitters and secondgeneration antipsychotics. Recently, glutamatergic approaches for the treatment of MDD have increasingly received attention, and preclinical research suggests that metabotropic glutamate receptor 5 (mGlu5) inhibitors have antidepressant-like properties. Basimglurant (2-chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine) is a novel mGlu5 negative allosteric modulator currently in phase 2 clinical development for MDD and fragile X syndrome. Here, the comprehensive preclinical pharmacological profile of basimglurant is presented with a focus on its therapeutic potential for MDD and drug-like properties. Basimglurant is a potent, selective, and safe mGlu5 inhibitor with good oral bioavailability and long half-life supportive of once-daily administration, good brain penetration, and high in vivo potency. It has antidepressant properties that are corroborated by its functional magnetic imaging profile as well as anxiolytic-like and antinociceptive features. In electroencephalography recordings, basimglurant shows wakepromoting effects followed by increased delta power during subsequent non-rapid eye movement sleep. In microdialysis studies, basimglurant had no effect on monoamine transmitter levels in the frontal cortex or nucleus accumbens except for a moderate increase of accumbal dopamine, which is in line with its lack of pharmacological activity on monoamine reuptake transporters. These data taken together, basimglurant has favorable drug-like properties, a differentiated molecular mechanism of action, and antidepressant-like features that suggest the possibility of also addressing important comorbidities of MDD including anxiety and pain as well as daytime sleepiness and apathy or lethargy.

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The role of metabotropic glutamate receptor mGlu5 in control of micturition and bladder nociception

Cited by 20 publications

References 27 publications

Expression of Vesicular Glutamate Transporters in Sensory and Autonomic Neurons Innervating the Mouse Bladder

Expression of Vesicular Glutamate Transporters in Sensory and Autonomic Neurons Innervating the Mouse Bladder

Visceral Pain

Pharmacology of Basimglurant (RO4917523, RG7090), a Unique Metabotropic Glutamate Receptor 5 Negative Allosteric Modulator in Clinical Development for Depression

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