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

Abstract

Background: Psychological stress is a risk factor for irritable bowel syndrome, a functional gastrointestinal pain disorder featuring abnormal brain-gut connectivity. The guanylate cyclase-C (GC-C) agonist linaclotide has been shown to relieve abdominal pain in IBS-C and exhibits antinociceptive effects in rodent models of post-inflammatory visceral hypersensitivity. However, the role GC-C signaling plays in psychological stress-induced visceral hypersensitivity is unknown. Here, we test the hypothesis that GC-C agonism reverses stress-induced colonic hypersensitivity via inhibition of nociceptive afferent signaling resulting in normalization of stress-altered corticotropin-releasing factor (CRF) expression in brain regions involved in pain perception and modulation. Methods: Adult female rats were exposed to water avoidance stress or sham stress for 10 days, and the effects of linaclotide on stress-induced changes in colonic sensitivity, corticolimbic phospho-extracellular signal-regulated kinase (pERK), and CRF expression were measured using a combination of behavioral assessments, immunohistochemistry, and qRT-PCR. Key Results: Stressed rats exhibited colonic hypersensitivity and elevated corticolimbic pERK on day 11, which was inhibited by linaclotide. qRT-PCR analysis revealed dysregulated CRF expression in the medial prefrontal cortex, paraventricular nucleus of the hypothalamus, and central nucleus of the amygdala on day 28. Dysregulated CRF expression was not affected by linaclotide treatment. Conclusions and Inferences: Our results demonstrate that exposure to repeated stress induces chronic colonic hypersensitivity in conjunction with altered corticolimbic activation and CRF expression. GC-C agonism attenuated stress-induced colonic hypersensitivity and ERK phosphorylation, but had no effect on CRF expression, suggesting the analgesic effects of linaclotide occur independent of stress-driven CRF gene expression in corticolimbic circuitry.

Linaclotide Reduced Response Time for Irritable Bowel Syndrome With Constipation Symptoms: Analysis of 4 Randomized Controlled Trials

“…The median time to an increase of ≥1 CSBM from baseline preceded the median time to abdominal symptom responses, but the median time to achieving a normal CSBM frequency (≥3 CSBMs/week) lagged slightly behind both abdominal pain and discomfort responses. This is consistent with known actions of linaclotide in preclinical models (26,27). Further supporting this concept, studies conducted with delayed release formulations of linaclotide, designed to be released in the distal ileum and colon, suggest that its analgesic and bowel modulatory actions may be mediated by 2 distinct guanylate cyclase C agonism pathways (21).…”

“…The median time to an increase of $1 CSBM from baseline preceded the median time to abdominal symptom responses, but the median time to achieving a normal CSBM frequency ($3 CSBMs/ week) lagged slightly behind both abdominal pain and discomfort responses. This is consistent with known actions of linaclotide in preclinical models (26,27). Further supporting this concept,…”

Guanylate cyclase-C agonists as peripherally acting treatments of chronic visceral pain

“…Similar antinociceptive actions of linaclotide (daily for 7 days) occur in neonatal rats exposed to unpredictable early life stress (ELS) [36], which also display increased mucosal permeability, an effect also reversed by linaclotide [36]. GC-C agonism also modulates corticolimbic activation and corticotropin-releasing factor signaling in a rat model of stress-induced colonic hypersensitivity [37].…”

Receptor Guanylyl Cyclase C and Cyclic GMP in Health and Disease: Perspectives and Therapeutic Opportunities

“…The GC-C-mediated regulation of visceral hypersensitivity has been studied using genetic models as well as pharmacological approaches. In preclinical models, GC-C agonism was shown to reduce post-inflammatory visceral hypersensitivity as well as stress-induced visceral hypersensitivity ( 126 , 142 ). Mechanistically, ligand-mediated activation of GC-C signaling in intestinal epithelial cells was found to release cGMP into the submucosa, where it inhibited nociceptive afferent signaling, or bottom-up sensitization, and mediated analgesic effect ( 126 , 141 ).…”