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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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UPEC Infection results in histological changes and bladder hyperalgesia. A. 24 hour infection with uropathogenic E. coli (UPEC) increases the VMR to bladder distention when compared to mock-infected (PBS) littermates. B. Infection with UPEC results in an increased infiltration of polymorphonuclear leukocytes (arrowheads), and a sloughing of the superficial facet cells. C. Distention alone does not result in the loss of superficial facet cells (arrows,). +/- SEM *p < 0.05, **p < 0.01, ***p < 0.001. Unpaired 2-way ANOVA with Bonferroni post-hoc test.
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Figure 5: UPEC Infection results in histological changes and bladder hyperalgesia. A. 24 hour infection with uropathogenic E. coli (UPEC) increases the VMR to bladder distention when compared to mock-infected (PBS) littermates. B. Infection with UPEC results in an increased infiltration of polymorphonuclear leukocytes (arrowheads), and a sloughing of the superficial facet cells. C. Distention alone does not result in the loss of superficial facet cells (arrows,). +/- SEM *p < 0.05, **p < 0.01, ***p < 0.001. Unpaired 2-way ANOVA with Bonferroni post-hoc test.

Mentions: Our results, together with previous studies [30,39,40] suggest that mGluR5 is involved in the mediation of micturition cycling and controls nociceptive responses during noxious bladder distention; however, the role of mGluR5 in inflammatory bladder nociception is unexplored. We therefore used the UPEC model of bladder inflammation to examine the role of mGluR5 in inflammatory bladder nociception. We found that UPEC infection resulted in an increased VMR to noxious bladder distention when compared to mock-infected littermate controls (Figure 5A, p < 0.0001). Furthermore, in mice whose bladders had been distended, UPEC infection produced an increased infiltration of polymorphonuclear leukocytes observed throughout the full thickness of the bladder tissue (Figure 5B, arrowheads), as well as an increased tissue thickness of both the urothelium and mesenchyme compared to distended mock-infected mice (Figure 5C). Noxious bladder distention combined with UPEC infection resulted in greater histological damage as measured by tissue inflammation scores when compared to mock-infected mice with noxious distention (data not shown) [41]. UPEC infection (alone and with distention) resulted in barrier disruption through a loss of superficial facet cells, while noxious distention alone had no effect on these cells and the barrier remained intact (arrows, Figure 5C).


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)

UPEC Infection results in histological changes and bladder hyperalgesia. A. 24 hour infection with uropathogenic E. coli (UPEC) increases the VMR to bladder distention when compared to mock-infected (PBS) littermates. B. Infection with UPEC results in an increased infiltration of polymorphonuclear leukocytes (arrowheads), and a sloughing of the superficial facet cells. C. Distention alone does not result in the loss of superficial facet cells (arrows,). +/- SEM *p < 0.05, **p < 0.01, ***p < 0.001. Unpaired 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 5: UPEC Infection results in histological changes and bladder hyperalgesia. A. 24 hour infection with uropathogenic E. coli (UPEC) increases the VMR to bladder distention when compared to mock-infected (PBS) littermates. B. Infection with UPEC results in an increased infiltration of polymorphonuclear leukocytes (arrowheads), and a sloughing of the superficial facet cells. C. Distention alone does not result in the loss of superficial facet cells (arrows,). +/- SEM *p < 0.05, **p < 0.01, ***p < 0.001. Unpaired 2-way ANOVA with Bonferroni post-hoc test.
Mentions: Our results, together with previous studies [30,39,40] suggest that mGluR5 is involved in the mediation of micturition cycling and controls nociceptive responses during noxious bladder distention; however, the role of mGluR5 in inflammatory bladder nociception is unexplored. We therefore used the UPEC model of bladder inflammation to examine the role of mGluR5 in inflammatory bladder nociception. We found that UPEC infection resulted in an increased VMR to noxious bladder distention when compared to mock-infected littermate controls (Figure 5A, p < 0.0001). Furthermore, in mice whose bladders had been distended, UPEC infection produced an increased infiltration of polymorphonuclear leukocytes observed throughout the full thickness of the bladder tissue (Figure 5B, arrowheads), as well as an increased tissue thickness of both the urothelium and mesenchyme compared to distended mock-infected mice (Figure 5C). Noxious bladder distention combined with UPEC infection resulted in greater histological damage as measured by tissue inflammation scores when compared to mock-infected mice with noxious distention (data not shown) [41]. UPEC infection (alone and with distention) resulted in barrier disruption through a loss of superficial facet cells, while noxious distention alone had no effect on these cells and the barrier remained intact (arrows, Figure 5C).

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