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Metabotropic glutamate receptor 5 (mGluR5) regulates bladder nociception.

Crock LW, Stemler KM, Song DG, Abbosh P, Vogt SK, Qiu CS, Lai HH, Mysorekar IU, Gereau RW - Mol Pain (2012)

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Neuroscience Program, Washington University School of Medicine, St, Louis, MO 63110, USA.

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.

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Related in: MedlinePlus

Fenobam treatment increases the intermicturition interval. A-C. Representative urodynamic profile of WT mice before and after treatment. An intraperitoneal (IP) injection with fenobam significantly increased the IMI in 4/8 mice treated (B, E), while 4/8 mice stopped cycling (C). In the mice that stopped cycling, the mean time to resume bladder cycling and micturition after IP fenobam administration was 18.6 ± 5.0 minutes. The IMI was not significantly affected by IP DMSO (n = 7) (A, D). *P < 0.05 paired Student's t-test compared to baseline.
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Figure 4: Fenobam treatment increases the intermicturition interval. A-C. Representative urodynamic profile of WT mice before and after treatment. An intraperitoneal (IP) injection with fenobam significantly increased the IMI in 4/8 mice treated (B, E), while 4/8 mice stopped cycling (C). In the mice that stopped cycling, the mean time to resume bladder cycling and micturition after IP fenobam administration was 18.6 ± 5.0 minutes. The IMI was not significantly affected by IP DMSO (n = 7) (A, D). *P < 0.05 paired Student's t-test compared to baseline.

Mentions: To determine if the voiding behavior we observed in mGluR5 KO mice was the result of genetic ablation of mGluR5 or the result of compensatory changes, we acutely treated WT mice with fenobam or vehicle and measured the effect on urodynamics. While vehicle treatment had no effect on IMI (160.2 seconds versus 177.1 seconds, for baseline and vehicle (DMSO) respectively, p = 0.66, Figure 4D), fenobam treatment increased the IMI when compared to the baseline IMI. The IMI before fenobam treatment was 182 seconds (n = 8). After IP fenobam treatment, four of the eight mice stopped bladder cycling and micturition immediately (Figure 4C), while four of the mice had significantly increased IMI (481.3 seconds, p = 0.031, Figure 4D and 4E). The mean time to resume bladder cycling and micturition after systemic fenobam administration was 18.6 minutes. This suggests a tight coupling between mGluR5 activation and micturition cycling. The acute effect of the mGluR5 antagonist also suggests that the increased IMI observed in mGluR5 KO mice is not likely due to developmental changes as a result of genetic ablation of mGluR5.


Metabotropic glutamate receptor 5 (mGluR5) regulates bladder nociception.

Crock LW, Stemler KM, Song DG, Abbosh P, Vogt SK, Qiu CS, Lai HH, Mysorekar IU, Gereau RW - Mol Pain (2012)

Fenobam treatment increases the intermicturition interval. A-C. Representative urodynamic profile of WT mice before and after treatment. An intraperitoneal (IP) injection with fenobam significantly increased the IMI in 4/8 mice treated (B, E), while 4/8 mice stopped cycling (C). In the mice that stopped cycling, the mean time to resume bladder cycling and micturition after IP fenobam administration was 18.6 ± 5.0 minutes. The IMI was not significantly affected by IP DMSO (n = 7) (A, D). *P < 0.05 paired Student's t-test compared to baseline.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3369204&req=5

Figure 4: Fenobam treatment increases the intermicturition interval. A-C. Representative urodynamic profile of WT mice before and after treatment. An intraperitoneal (IP) injection with fenobam significantly increased the IMI in 4/8 mice treated (B, E), while 4/8 mice stopped cycling (C). In the mice that stopped cycling, the mean time to resume bladder cycling and micturition after IP fenobam administration was 18.6 ± 5.0 minutes. The IMI was not significantly affected by IP DMSO (n = 7) (A, D). *P < 0.05 paired Student's t-test compared to baseline.
Mentions: To determine if the voiding behavior we observed in mGluR5 KO mice was the result of genetic ablation of mGluR5 or the result of compensatory changes, we acutely treated WT mice with fenobam or vehicle and measured the effect on urodynamics. While vehicle treatment had no effect on IMI (160.2 seconds versus 177.1 seconds, for baseline and vehicle (DMSO) respectively, p = 0.66, Figure 4D), fenobam treatment increased the IMI when compared to the baseline IMI. The IMI before fenobam treatment was 182 seconds (n = 8). After IP fenobam treatment, four of the eight mice stopped bladder cycling and micturition immediately (Figure 4C), while four of the mice had significantly increased IMI (481.3 seconds, p = 0.031, Figure 4D and 4E). The mean time to resume bladder cycling and micturition after systemic fenobam administration was 18.6 minutes. This suggests a tight coupling between mGluR5 activation and micturition cycling. The acute effect of the mGluR5 antagonist also suggests that the increased IMI observed in mGluR5 KO mice is not likely due to developmental changes as a result of genetic ablation of mGluR5.

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Neuroscience Program, Washington University School of Medicine, St, Louis, MO 63110, USA.

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.

Show MeSH
Related in: MedlinePlus