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

Reduced visceromotor response to bladder distension in mGluR5 knockout mice compared to wild type littermates. A. Representative VMR tracings from a WT and mGluR5 KO mice. As the intravesicular pressure is increased (20-80 mmHg), the EMG activity of the abdominal muscle (VMR) is also increased. The total amount of activity (area under the curve) during the 20 second distention is calculated to determine the evoked response at each pressure. B. mGluR5 KO (n = 18) mice have a significantly blunted VMR when compared to WT littermates (n = 15) +/- SEM,* p < 0.05, **p < 0.01, ***p < 0.001. 2-way ANOVA with Bonferroni post-hoc test. There were no obvious histological differences observed between mGluR5 KO mice (1D) and their WT littermates (1C). In both, the urothelium (above dashed line) has normal layers of superficial facet cells (arrows), intermediate cells (black arrowhead) and basal cells (white arrowhead).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Reduced visceromotor response to bladder distension in mGluR5 knockout mice compared to wild type littermates. A. Representative VMR tracings from a WT and mGluR5 KO mice. As the intravesicular pressure is increased (20-80 mmHg), the EMG activity of the abdominal muscle (VMR) is also increased. The total amount of activity (area under the curve) during the 20 second distention is calculated to determine the evoked response at each pressure. B. mGluR5 KO (n = 18) mice have a significantly blunted VMR when compared to WT littermates (n = 15) +/- SEM,* p < 0.05, **p < 0.01, ***p < 0.001. 2-way ANOVA with Bonferroni post-hoc test. There were no obvious histological differences observed between mGluR5 KO mice (1D) and their WT littermates (1C). In both, the urothelium (above dashed line) has normal layers of superficial facet cells (arrows), intermediate cells (black arrowhead) and basal cells (white arrowhead).

Mentions: To assess bladder nociception in response to distension, we utilized the distension-evoked visceromotor response (VMR). The VMR is a spinobulbospinal reflex to bladder distention, increased in decerebrate mice/rats and absent in mice/rats with an acute mid thoracic spinal cord transection [32-34]. Bladder distention reliably produces pain and/or discomfort in humans [35], and is frequently used in rodents as a visceral pain model [5,30,33]. To provide genetic evidence supporting a role for mGluR5 in bladder nociception, we tested the VMR to bladder distention in mGluR5 knockout mice (mGluR5 KO) compared to their WT littermates. Stepwise increases in bladder distension resulted in progressively larger VMR in wild type mice, as shown in Figure 1B. Furthermore, mGluR5 KO mice showed a statistically significant decrease in the evoked response to bladder distention (VMR) in the noxious range of pressures when compared to the VMR of WT littermates (p < 0.0001).


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)

Reduced visceromotor response to bladder distension in mGluR5 knockout mice compared to wild type littermates. A. Representative VMR tracings from a WT and mGluR5 KO mice. As the intravesicular pressure is increased (20-80 mmHg), the EMG activity of the abdominal muscle (VMR) is also increased. The total amount of activity (area under the curve) during the 20 second distention is calculated to determine the evoked response at each pressure. B. mGluR5 KO (n = 18) mice have a significantly blunted VMR when compared to WT littermates (n = 15) +/- SEM,* p < 0.05, **p < 0.01, ***p < 0.001. 2-way ANOVA with Bonferroni post-hoc test. There were no obvious histological differences observed between mGluR5 KO mice (1D) and their WT littermates (1C). In both, the urothelium (above dashed line) has normal layers of superficial facet cells (arrows), intermediate cells (black arrowhead) and basal cells (white arrowhead).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Reduced visceromotor response to bladder distension in mGluR5 knockout mice compared to wild type littermates. A. Representative VMR tracings from a WT and mGluR5 KO mice. As the intravesicular pressure is increased (20-80 mmHg), the EMG activity of the abdominal muscle (VMR) is also increased. The total amount of activity (area under the curve) during the 20 second distention is calculated to determine the evoked response at each pressure. B. mGluR5 KO (n = 18) mice have a significantly blunted VMR when compared to WT littermates (n = 15) +/- SEM,* p < 0.05, **p < 0.01, ***p < 0.001. 2-way ANOVA with Bonferroni post-hoc test. There were no obvious histological differences observed between mGluR5 KO mice (1D) and their WT littermates (1C). In both, the urothelium (above dashed line) has normal layers of superficial facet cells (arrows), intermediate cells (black arrowhead) and basal cells (white arrowhead).
Mentions: To assess bladder nociception in response to distension, we utilized the distension-evoked visceromotor response (VMR). The VMR is a spinobulbospinal reflex to bladder distention, increased in decerebrate mice/rats and absent in mice/rats with an acute mid thoracic spinal cord transection [32-34]. Bladder distention reliably produces pain and/or discomfort in humans [35], and is frequently used in rodents as a visceral pain model [5,30,33]. To provide genetic evidence supporting a role for mGluR5 in bladder nociception, we tested the VMR to bladder distention in mGluR5 knockout mice (mGluR5 KO) compared to their WT littermates. Stepwise increases in bladder distension resulted in progressively larger VMR in wild type mice, as shown in Figure 1B. Furthermore, mGluR5 KO mice showed a statistically significant decrease in the evoked response to bladder distention (VMR) in the noxious range of pressures when compared to the VMR of WT littermates (p < 0.0001).

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