2. Academic Validation
  3. TGR5 agonists induce peripheral and central hypersensitivity to bladder distension

TGR5 agonists induce peripheral and central hypersensitivity to bladder distension

  • Sci Rep. 2022 Jun 15;12(1):9920. doi: 10.1038/s41598-022-14195-w.
Ashlee Caldwell  # 1 2 3,  Luke Grundy  # 1 2,  Andrea M Harrington 1 2,  Sonia Garcia-Caraballo 1 2,  Joel Castro 1 2,  Nigel W Bunnett 4,  Stuart M Brierley 5 6 7
Affiliations

Affiliations

  • 1 Visceral Pain Research Group, College of Medicine and Public Health, Flinders Health and Medical Research Institute (FHMRI), Flinders University, Bedford Park, South Australia, 5042, Australia.
  • 2 Hopwood Centre for Neurobiology, Lifelong Health Theme, Level 7, South Australian Health and Medical Research Institute (SAHMRI), North Terrace, Adelaide, South Australia, 5000, Australia.
  • 3 Discipline of Medicine, University of Adelaide, Level 7, SAHMRI, North Terrace, Adelaide, South Australia, 5000, Australia.
  • 4 Department of Molecular Pathobiology, Department of Neuroscience and Physiology, Neuroscience Institute, New York University, New York, NY, USA.
  • 5 Visceral Pain Research Group, College of Medicine and Public Health, Flinders Health and Medical Research Institute (FHMRI), Flinders University, Bedford Park, South Australia, 5042, Australia. stuart.brierley@flinders.edu.au.
  • 6 Hopwood Centre for Neurobiology, Lifelong Health Theme, Level 7, South Australian Health and Medical Research Institute (SAHMRI), North Terrace, Adelaide, South Australia, 5000, Australia. stuart.brierley@flinders.edu.au.
  • 7 Discipline of Medicine, University of Adelaide, Level 7, SAHMRI, North Terrace, Adelaide, South Australia, 5000, Australia. stuart.brierley@flinders.edu.au.
  • # Contributed equally.
PMID: 35705684 DOI: 10.1038/s41598-022-14195-w
Abstract

The mechanisms underlying chronic bladder conditions such as interstitial cystitis/bladder pain syndrome (IC/BPS) and overactive bladder syndrome (OAB) are incompletely understood. However, targeting specific receptors mediating neuronal sensitivity to specific stimuli is an emerging treatment strategy. Recently, irritant-sensing receptors including the bile acid receptor TGR5, have been identified within the viscera and are thought to play a key role in neuronal hypersensitivity. Here, in mice, we identify mRNA expression of TGR5 (Gpbar1) in all layers of the bladder as well as in the lumbosacral dorsal root ganglia (DRG) and in isolated bladder-innervating DRG neurons. In bladder-innervating DRG neurons Gpbar1 mRNA was 100% co-expressed with Trpv1 and 30% co-expressed with Trpa1. In vitro live-cell calcium imaging of bladder-innervating DRG neurons showed direct activation of a sub-population of bladder-innervating DRG neurons with the synthetic TGR5 agonist CCDC, which was diminished in Trpv1-/- but not Trpa1-/- DRG neurons. CCDC also activated a small percentage of non-neuronal cells. Using an ex vivo mouse bladder afferent recording preparation we show intravesical application of endogenous (5α-pregnan-3β-ol-20-one sulphate, Pg5α) and synthetic (CCDC) TGR5 agonists enhanced afferent mechanosensitivity to bladder distension. Correspondingly, in vivo intravesical administration of CCDC increased the number of spinal dorsal horn neurons that were activated by bladder distension. The enhanced mechanosensitivity induced by CCDC ex vivo and in vivo was absent using Gpbar1-/- mice. Together, these results indicate a role for the TGR5 receptor in mediating bladder afferent hypersensitivity to distension and thus may be important to the symptoms associated with IC/BPS and OAB.

Figures
Products