Central amygdala metabotropic glutamate receptor 5 in the modulation of visceral pain.
Painful bladder syndrome is a debilitating condition that affects 3-6% of women in the United States. Multiple lines of evidence suggest that changes in CNS processing are key to the development of chronic bladder pain conditions but little is known regarding the underlying cellular, molecular, and neuronal mechanisms. Using a mouse model of distention-induced bladder pain, we found that the central nucleus of the amygdala (CeA) is a critical site of neuromodulation for processing of bladder nociception. Furthermore, we demonstrate that metabotropic glutamate receptor 5 (mGluR5) activation in the CeA induces bladder pain sensitization by increasing CeA output. Thus, pharmacological activation of mGluR5 in the CeA is sufficient to increase the response to bladder distention. Additionally, pharmacological blockade or virally mediated conditional deletion of mGluR5 in the CeA reduced responses to bladder distention suggesting that mGluR5 in the CeA is also necessary for these responses. Finally, we used optogenetic activation of the CeA and demonstrated that this caused a robust increase in the visceral pain response. The CeA-localized effects on responses to bladder distention are associated with changes in extracellular signal-regulated kinases 1/2 (ERK1/2) phosphorylation in the spinal cord. Overall, these data demonstrate that mGluR5 activation leads to increased CeA output that drives bladder pain sensitization.
Program in Neuroscience, Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Lara W
LW
Crock
Benedict J
BJ
Kolber
Clinton D
CD
Morgan
Katelyn E
KE
Sadler
Sherri K
SK
Vogt
Michael R
MR
Bruchas
Robert W
RW
Gereau
D000679:Amygdala / Q000502:physiology*; D000818:Animals; D005260:Female; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010147:Pain Measurement / Q000379:methods; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000502:physiology*; D059265:Visceral Pain / Q000235:genetics / Q000378:metabolism*
C578936:Grm5 protein, mouse; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate