Metabotropic Glutamate Receptor 5 (mGluR5) Regulates Bladder Nociception

Abstract

Background: Interstitial cystitis/painful bladder syndrome (IC/PBS), is a severely debilitating chronic condition that is frequently unresponsive to conventional pain medications. The etiology is unknown, however evidence suggests that nervous system sensitization contributes to enhanced pain in IC/PBS. In particular, central nervous system plasticity of glutamatergic signaling involving NMDA and metabotropic glutamate receptors (mGluRs) has been implicated in a variety of chronic pain conditions. Here, we test the hypothesis that mGluR5 mediates both non-inflammatory and inflammatory bladder pain or nociception in a mouse model by monitoring the visceromotor response (VMR) during graded bladder distention. Results: Using a combination of genetic and pharmacologic approaches, we provide evidence indicating that mGluR5 is necessary for the full expression of VMR in response to bladder distention in the absence of inflammation. Furthermore, we observed that mice infected with a uropathogenic strain of Escherichia coli (UPEC) develop inflammatory hyperalgesia to bladder distention, and that the selective mGluR5 antagonist fenobam [N-(3-chlorophenyl)-N′-(4,5-dihydro-1-methyl-4-oxo-1H-imidazole-2-yl) urea], reduces the VMR to bladder distention in UPEC-infected mice. Conclusions: Taken together, these data suggest that mGluR5 modulates both inflammatory and non-inflammatory bladder nociception, and highlight the therapeutic potential for mGluR5 antagonists in the alleviation of bladder pain.

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

“…Furthermore, basimglurant showed antinociceptive activity in the formalin pain and cold allodynia procedures. Basimglurant also normalized the urine bladder function in rodent models of overactive bladder, confirming previous work with other mGlu5 NAMs (Crock et al, 2012) and suggesting the possibility of benefits in the context of visceral pain. Taken together, these results indicate that basimglurant has the potential to address two important comorbidities of depression: anxiety and somatic pain.…”

Protamine Sulfate Induced Bladder Injury Protects from Distention Induced Bladder Pain

“…We have previously used the visceromotor response (VMR) to reliably measure hypersensitivity in a chemically-induced bladder inflammation model, demonstrating that the VMR is potentiated by inflammation (mustard oil, cyclophosphamide, and zymosan) and inhibited by analgesics (morphine and intravesicular lidocaine). 11–13 The abdominal VMR is measured as the electromyographic signals of the external oblique muscle. Behaviorally, it corresponds to abdominal withdrawal and nocifensive guarding when an animal experiences pain while its bladder is distended.…”

“…Visceral nociception was quantified by an electromyographic recording of the abdominal muscle response to bladder distention as described previously. 11–13 For each distention, the VMR signals were subtracted from the baseline, rectified, and integrated over 20 seconds to quantify the area under the curve.…”

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

“…Glutamate, which is contained in the central terminals of primary afferents, spinal interneurons and terminals of fibers that descend from the medulla oblongata, 27 is well established as important for nociceptive transmission from pelvic organs. 1,28 Thus, complex interaction was noted between spinal ionotropic (NMDA and AMPA) receptors in the spinal processing of nociceptive input from the irritated lower urinary tract. 29 Likewise, a facilitatory role in bladder primary afferent processing was attributable to metabotropic glutamate receptor 5 in normal conditions and during lower urinary tract inflammation.…”

“…29 Likewise, a facilitatory role in bladder primary afferent processing was attributable to metabotropic glutamate receptor 5 in normal conditions and during lower urinary tract inflammation. 28 However, the role of peripheral glutamate release in the bladder is unclear. Thus, the intravesical application of metabotropic glutamate receptor antagonists has no effect on bladder contractility and pelvic nerve afferent firing in normal rats.…”