Linaclotide Attenuates Visceral Organ Crosstalk: Role of Guanylate Cyclase-C Activation in Reversing Bladder-Colon Cross-Sensitization

Abstract

Bladder pain syndrome (BPS) is poorly understood; however, there is a female predominance and comorbidity 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. We showed previously that infusion of dilute protamine sulfate (PS) into the bladder increased sensitivity and permeability in the bladder and colon. PS was infused into the bladder of female rats; 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 to graded pressures of colorectal distension (CRD). Permeability was measured in vitro via transepithelial electrical resistance (TEER) and conductance (G). Linaclotide (3 g/kg, p.o.) or vehicle was administered daily for 7 days prior to experiments. Rats treated with PS bladder infusion exhibited visceral hyperalgesia, as shown by a significantly higher response frequency to individual von Frey filaments and increased behavioral responses to CRD. Linaclotide attenuated bladder and colonic hyperalgesia to control levels. PS infusion into the bladder 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. Our findings suggest a novel treatment paradigm for GC-C agonism in IBS-C and BPS mediated through a mechanism involving visceral organ crosstalk.

Experimentally Induced Bladder Permeability Evokes Bladder Afferent Hypersensitivity in the Absence of Inflammation

“…Our data show that increasing bladder permeability with protamine sulfate in the absence of inflammation induces hypersensitivity of bladder afferents to graded bladder distension. It is likely these changes in bladder afferent sensitivity are responsible for the pelvic sensitivity observed in response to suprapubic stimulation following protamine sulfate treatment (Mohammadi et al, 2018). We also observed increased peak firing of single units 1-day after protamine sulfate treatment, as well as a trend toward decreased afferent activation thresholds and an increase in the ratio of low-threshold afferents.…”

“…We also show that bladder afferent responses are maintained at control levels 28-days post-protamine sulfate, suggesting secondary hypersensitivity is not occurring in these conditions. A number of previous studies have provided indirect evidence that changes in bladder permeability can induce sensory dysfunction (Keay et al, 2014;Hurst et al, 2015;Grundy et al, 2018a;Mohammadi et al, 2018), however, it remained to be determined if bladder permeability is part of the underlying pathology of visceral hypersensitivity disorders such as IC/BPS, or an unavoidable consequence of inflammation (Grundy et al, 2019a). Our data show that increasing bladder permeability with protamine sulfate in the absence of inflammation induces hypersensitivity of bladder afferents to graded bladder distension.…”

“…The protamine sulfate model used was ostensibly as described previously (Greenwood-Van Meerveld et al, 2015;Mohammadi et al, 2018). These studies have shown that bladders from protamine sulfate-treated animals showed signs of oedema at 1-5 days post infusion, but the urothelium remains intact with no damage to the umbrella cells.…”

Peripheral Guanylate Cyclase‐C modulation of corticolimbic activation and corticotropin‐releasing factor signaling in a rat model of stress‐induced colonic hypersensitivity

“…*** p < 0.001, **** p < 0.0001 vs. SHAM, ### p < 0.001 vs. WAS +vehicle, two-factor repeated-measures ANOVA with the Bonferroni post hoc test or unpaired t test post-inflammatory visceral hypersensitivity and visceral organ crosstalk-both of which involve "bottom-up" sensitization. 27,28,38 We have also demonstrated the ability of peripheral GC-C agonism to attenuate visceral hypersensitivity in a female-predominant model of early life stress. 29 However, the mechanism(s) by which linaclotide reduces centrally driven colonic hypersensitivity induced by stress in adulthood remains largely unexplored.…”

“…27 These antinociceptive effects have been observed in models of post-inflammatory visceral hypersensitivity and visceral organ crosstalk. 27,28 Importantly, linaclotide also attenuates stress-induced visceral hypersensitivity, suggesting linaclotide is capable of relieving abdominal pain in patients whose symptoms are exacerbated by stress. 29,30 However, it is unknown whether GC-C agonism affects visceral nociception by modulating stress-altered neuronal activation and CRF signaling within stress-responsive corticolimbic circuits in the brain in combination with inhibition of visceral afferent sensitization in the periphery.…”