Moderated Poster

Poster, Podium & Video Sessions

MP42-05: Chronic oral administration of the guanylate cyclase-C agonist linaclotide attenuates colitis induced bladder afferent and dorsal root ganglion hyperactivity

Saturday, May 13
3:30 PM - 5:30 PM
Location: BCEC: Room 160

Presentation Authors: Luke Grundy*, Sonia Garcia-Caraballo, Jessica Maddern, Grigori Rychkov, Adelaide, Australia, Pei Ge, Gerhard Hannig, Caroline Kurtz, Ada Silos-Santiago, Cambridge, MA, Stuart Brierley, Adelaide, Australia

Introduction: Patients suffering from IBS frequently suffer from urological symptoms characteristic of overactive bladder and interstitial cystitis. Cross-organ sensitisation between the bowel and bladder has also been described in pre-clinical studies. Rodents with active colitis exhibit bladder afferent sensitisation and altered cystometry [1,2]. We have previously shown in a model of chronic colonic hypersensitivity (CCH) that bladder mechanical hypersensitivity persists following the resolution of colitis, and that linaclotide, an FDA approved guanylate cyclase-C (GC-C) agonist, is able to attenuate these changes [3]. We hypothesise that these CCH-induced changes are the result of altered sensitivity of afferents both within the colon and bladder wall and within the dorsal root ganglion (DRG), and that oral linaclotide administration may act to reduce this hypersensitivity.

Methods: We investigated healthy C57BL/6J mice and mice with CCH, 28 days after intra-colonic TNBS administration. CCH mice were randomly assigned to either chronic linaclotide (3μg/kg/day) or placebo (water) administration, consisting of a once daily oral gavage for 2 weeks prior to experimentation. Ex-vivo electrophysiological recordings determined bladder afferent and contractile sensitivity to αβMe-ATP (30μM), carbachol (1μM), and capsaicin (10μM) as well as whole cell patch clamp of retrogradely traced bladder DRG neurons in all four groups.

Results: Bladder DRG from mice with CCH display hyperexcitability, with a significant reduction in rheobase compared to controls (p≤0.01). CCH mice also display significantly enhanced afferent responses to αβMe-ATP (p≤0.001), carbachol (p≤0.001), and capsaicin (p≤0.001). CCH mice treated with linaclotide display attenuated DRG hyperexcitability and normalised afferent responses to agonists (p≤0.01) compared to placebo (p≤0.01).

Conclusions: Mice with CCH also display increased bladder afferent excitability within both the DRG and bladder wall, indicating cross-organ sensitisation. Chronic oral administration of linaclotide, a locally acting GC-C agonist that inhibits colonic nociceptors, reverses these colitis-induced changes in bladder afferent sensitivity. Common sensory pathways may allow agents that reduce abdominal pain to improve urological symptoms. 1. Lamb, K., et al. AJPGI, 2006. 2. Ustinova et al, Neurourology and Urodynamics, 2010. 3. Grundy, L., et al., MP28-06. The Journal of Urology, 2016.



Source Of Funding: NHMRC Australia, Ironwood Pharmaceuticals

Send Email for Luke Grundy


Assets

MP42-05: Chronic oral administration of the guanylate cyclase-C agonist linaclotide attenuates colitis induced bladder afferent and dorsal root ganglion hyperactivity



Attendees who have favorited this

Send Email for Chronic oral administration of the guanylate cyclase-C agonist linaclotide attenuates colitis induced bladder afferent and dorsal root ganglion hyperactivity