PT  - JOURNAL ARTICLE
AU  - Ehsan N Mohammadi
AU  - Casey O. Ligon
AU  - Ada Silos-Santiago
AU  - Pei Ge
AU  - Caroline Kurtz
AU  - Carolyn Higgins
AU  - Gerhard Hannig
AU  - Beverley Greenwood-Van Meerveld
TI  - Linaclotide Attenuates Visceral Organ Crosstalk: Role of Guanylate Cyclase C Activation in Reversing Bladder-Colon Cross Sensitization
AID  - 10.1124/jpet.118.248567
DP  - 2018 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - jpet.118.248567
4099  - http://jpet.aspetjournals.org/content/early/2018/05/21/jpet.118.248567.short
4100  - http://jpet.aspetjournals.org/content/early/2018/05/21/jpet.118.248567.full
AB  - Introduction: Bladder pain syndrome (BPS) is poorly understood, however there is evidence of a female predominance and co-morbidity with irritable bowel syndrome (IBS). Here we test the hypothesis that linaclotide, a guanylate cyclase-C (GC-C) agonist approved for the treatment of IBS with constipation (IBS-C), may represent a novel therapeutic for BPS acting through a mechanism involving an inhibition of visceral organ cross sensitization. Methods: In female rats, infusion of dilute protamine sulfate (PS) into the bladder was employed to induce bladder and colonic hypersensitivity. Bladder sensitivity was assessed via application of von Frey filaments applied to the suprapubic area and the frequency of withdrawal responses was recorded. Colonic sensitivity was measured via visceromotor behavioral response (VMR) to graded pressures of colorectal distension (CRD). PS-induced bladder and colonic hyperpermeability was measured in vitro via transepithelial electrical resistance (TEER) and conductance (G). Linaclotide (3 µg/kg p.o.) or vehicle was administered daily for 7 days prior to experiments. Results: PS-bladder treated rats exhibited visceral hyperalgesia as shown by a significantly higher response frequency to individual von Frey filaments and increased behavioral responses to colonic distension. Linaclotide attenuated bladder and colonic hyperalgesia to levels resembling controls. PS infusion into the bladder significantly increased bladder and colon permeability measured as a decrease in TEER and increased G. Linaclotide significantly inhibited PS-induced colonic hyperpermeability while having no effect on bladder hyperpermeability. Summary and Conclusion: Our findings suggest a novel treatment paradigm for GC-C agonism in IBS-C and BPS mediated through visceral organ crosstalk, a mechanism not previously linked to linaclotide.