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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

Treatment with an mGluR5 antagonist, fenobam, is analgesic in a UPEC infection-induced inflammatory bladder distention-evoked pain model. Treatment with the vehicle used to dissolve fenobam (100% DMSO) increases the evoked response to bladder distention (A, n = 5), whereas treatment with fenobam significantly reduced the evoked response to bladder distension (B, n = 7). In mock-infected animals, treatment with the vehicle used to dissolve fenobam (100% DMSO) had no effect on the evoked response (C, n = 6), whereas fenobam significantly reduced the evoked response (D, n = 6). * p < 0.05, **p < 0.01, ***p < 0.001. Paired 2-way ANOVA with Bonferroni post-hoc test
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Figure 6: Treatment with an mGluR5 antagonist, fenobam, is analgesic in a UPEC infection-induced inflammatory bladder distention-evoked pain model. Treatment with the vehicle used to dissolve fenobam (100% DMSO) increases the evoked response to bladder distention (A, n = 5), whereas treatment with fenobam significantly reduced the evoked response to bladder distension (B, n = 7). In mock-infected animals, treatment with the vehicle used to dissolve fenobam (100% DMSO) had no effect on the evoked response (C, n = 6), whereas fenobam significantly reduced the evoked response (D, n = 6). * p < 0.05, **p < 0.01, ***p < 0.001. Paired 2-way ANOVA with Bonferroni post-hoc test

Mentions: In mice with a UPEC-induced UTI, mice treated with vehicle had an increased VMR when compared to baseline (Figure 6A, p = 0.0007). While vehicle treatment increased the VMR, treatment with fenobam resulted in a significantly reduced VMR when compared to pre-fenobam measurements (Figure 6B, p = 0.0006). In contrast, vehicle had no effect on the VMR in mice mock infected (with PBS instead of UPEC, Figure 6C). In these control mice (mock infected), treatment with fenobam significantly reduced the VMR when compared to pre-treatment VMR measurements (Figure 6D). These results are consistent with those observed in WT mice (not mock-infected, Figures Error! Reference source not found. A and 2B).


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)

Treatment with an mGluR5 antagonist, fenobam, is analgesic in a UPEC infection-induced inflammatory bladder distention-evoked pain model. Treatment with the vehicle used to dissolve fenobam (100% DMSO) increases the evoked response to bladder distention (A, n = 5), whereas treatment with fenobam significantly reduced the evoked response to bladder distension (B, n = 7). In mock-infected animals, treatment with the vehicle used to dissolve fenobam (100% DMSO) had no effect on the evoked response (C, n = 6), whereas fenobam significantly reduced the evoked response (D, n = 6). * p < 0.05, **p < 0.01, ***p < 0.001. Paired 2-way ANOVA with Bonferroni post-hoc test
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 6: Treatment with an mGluR5 antagonist, fenobam, is analgesic in a UPEC infection-induced inflammatory bladder distention-evoked pain model. Treatment with the vehicle used to dissolve fenobam (100% DMSO) increases the evoked response to bladder distention (A, n = 5), whereas treatment with fenobam significantly reduced the evoked response to bladder distension (B, n = 7). In mock-infected animals, treatment with the vehicle used to dissolve fenobam (100% DMSO) had no effect on the evoked response (C, n = 6), whereas fenobam significantly reduced the evoked response (D, n = 6). * p < 0.05, **p < 0.01, ***p < 0.001. Paired 2-way ANOVA with Bonferroni post-hoc test
Mentions: In mice with a UPEC-induced UTI, mice treated with vehicle had an increased VMR when compared to baseline (Figure 6A, p = 0.0007). While vehicle treatment increased the VMR, treatment with fenobam resulted in a significantly reduced VMR when compared to pre-fenobam measurements (Figure 6B, p = 0.0006). In contrast, vehicle had no effect on the VMR in mice mock infected (with PBS instead of UPEC, Figure 6C). In these control mice (mock infected), treatment with fenobam significantly reduced the VMR when compared to pre-treatment VMR measurements (Figure 6D). These results are consistent with those observed in WT mice (not mock-infected, Figures Error! Reference source not found. A and 2B).

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