Metabotropic glutamate receptor 5 (mGluR5) regulates bladder nociception

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.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.Interstitial cystitis/painful bladder syndrome (IC/PBS) is a serious and painful condition of unknown etiology that affects 3-6% of women in the United States [1,2]. The major clinical symptom of IC/PBS is pain upon bladder filling (distention) leading to urinary frequency and urinary urgency [3]. The current available treatments are often ineffective and do not treat the underlying pathology. Rodent bladder-injury models that induce some of the symptoms observed in IC/PBS have been used to evaluate potential treatments for IC/PBS [4-9]. One injury model, bacterial cystitis (urinary tract infection, UTI) is known to cause a similar constellation of symptoms as observed in IC/PBS (i.e. urinary frequency and urgency [10-12]). In addition, bacterial cystitis can be modeled in rodents through bladder exposure to uropathogenic Escherichia Coli (UPEC) [13,14]. Bladder infections due to UPEC are responsible for approximately 80% of UTIs in otherwise healthy women [15,16]. Understanding the underlying molecular mechanisms of both non-inflammatory bladder pain and inflammatory bladder pain due to UPEC infection could lead to the development of novel treatments for painful bladder infections as well as for IC/PBS and po