Limits...
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.

Show MeSH

Related in: MedlinePlus

The selective mGluR5 antagonist, fenobam, is analgesic in distention-induced bladder pain model. A. Treatment with the vehicle used to dissolve fenobam (100% DMSO) has no effect on the response to bladder distention. B. Treatment with an mGluR5 antagonist, fenobam, is analgesic in a bladder distention-evoked pain model. C&D. Fenobam and DMSO reduce the evoked response in mGluR5 KO mice. +/- SEM,* p < 0.05, **p < 0.01, ***p < 0.001. 2-way ANOVA with Bonferroni post-hoc test.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3369204&req=5

Figure 2: The selective mGluR5 antagonist, fenobam, is analgesic in distention-induced bladder pain model. A. Treatment with the vehicle used to dissolve fenobam (100% DMSO) has no effect on the response to bladder distention. B. Treatment with an mGluR5 antagonist, fenobam, is analgesic in a bladder distention-evoked pain model. C&D. Fenobam and DMSO reduce the evoked response in mGluR5 KO mice. +/- SEM,* p < 0.05, **p < 0.01, ***p < 0.001. 2-way ANOVA with Bonferroni post-hoc test.

Mentions: Compensatory changes in gene expression represent a potential confound to any experiment utilizing genetic manipulation. Thus, the robust phenotype observed in the mGluR5 KO mice could be the result of compensatory expression changes in other genes that have a role in bladder nociception. An acute pharmacological blockade of the receptor represents a potentially powerful approach to complement these findings from genetically modified mice. However, as mentioned above, the pharmacologic agent (MPEP) used in prior studies shows a clear lack of specificity in vivo [31]. To ask whether mGluR5 activation is acutely involved in distention-induced bladder nociception, we tested whether specific pharmacologic inhibition of mGluR5 with the selective antagonist fenobam [31,37,38], would suppress the VMR to urinary bladder distention. Systemic (intraperitoneal (IP)) administration of fenobam to WT mice resulted in a statistically significant reduction in the response to bladder distention compared to pretreatment baseline responses (Figure 2B, p < 0.0001), whereas treatment with vehicle had no statistically significant effect on VMR compared to baseline (Figure 2A). Thus, pretreatment with fenobam mimicked the reduced nociceptive response to bladder distention that was observed in mGluR5 KO mice relative to their WT littermates (compare Figure 1A and 2A). We next evaluated the effect of fenobam on the VMR of mGluR5 KO mice. Surprisingly, treatment with either vehicle (DMSO) or fenobam caused a small but statistically significant decrease in the VMR evoked by bladder distention compared to baseline responses in mGluR5 KO mice (Figure 2C and 2D, p < 0.001 and p = 0.007).


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)

The selective mGluR5 antagonist, fenobam, is analgesic in distention-induced bladder pain model. A. Treatment with the vehicle used to dissolve fenobam (100% DMSO) has no effect on the response to bladder distention. B. Treatment with an mGluR5 antagonist, fenobam, is analgesic in a bladder distention-evoked pain model. C&D. Fenobam and DMSO reduce the evoked response in mGluR5 KO mice. +/- SEM,* p < 0.05, **p < 0.01, ***p < 0.001. 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 2: The selective mGluR5 antagonist, fenobam, is analgesic in distention-induced bladder pain model. A. Treatment with the vehicle used to dissolve fenobam (100% DMSO) has no effect on the response to bladder distention. B. Treatment with an mGluR5 antagonist, fenobam, is analgesic in a bladder distention-evoked pain model. C&D. Fenobam and DMSO reduce the evoked response in mGluR5 KO mice. +/- SEM,* p < 0.05, **p < 0.01, ***p < 0.001. 2-way ANOVA with Bonferroni post-hoc test.
Mentions: Compensatory changes in gene expression represent a potential confound to any experiment utilizing genetic manipulation. Thus, the robust phenotype observed in the mGluR5 KO mice could be the result of compensatory expression changes in other genes that have a role in bladder nociception. An acute pharmacological blockade of the receptor represents a potentially powerful approach to complement these findings from genetically modified mice. However, as mentioned above, the pharmacologic agent (MPEP) used in prior studies shows a clear lack of specificity in vivo [31]. To ask whether mGluR5 activation is acutely involved in distention-induced bladder nociception, we tested whether specific pharmacologic inhibition of mGluR5 with the selective antagonist fenobam [31,37,38], would suppress the VMR to urinary bladder distention. Systemic (intraperitoneal (IP)) administration of fenobam to WT mice resulted in a statistically significant reduction in the response to bladder distention compared to pretreatment baseline responses (Figure 2B, p < 0.0001), whereas treatment with vehicle had no statistically significant effect on VMR compared to baseline (Figure 2A). Thus, pretreatment with fenobam mimicked the reduced nociceptive response to bladder distention that was observed in mGluR5 KO mice relative to their WT littermates (compare Figure 1A and 2A). We next evaluated the effect of fenobam on the VMR of mGluR5 KO mice. Surprisingly, treatment with either vehicle (DMSO) or fenobam caused a small but statistically significant decrease in the VMR evoked by bladder distention compared to baseline responses in mGluR5 KO mice (Figure 2C and 2D, p < 0.001 and p = 0.007).

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