Abstract
Irritable bowel syndrome (IBS) is a brain-gut disorder characterized by abdominal pain and altered bowel habits. Although the etiology of IBS remains unclear, stress in adulthood or in early life has been shown to be a significant factor in the development of IBS symptomatology. Evidence suggests that aberrant calcitonin gene-related peptide (CGRP) signaling may be involved in afferent sensitization and visceral organ hypersensitivity. Here, we used a monoclonal anti-CGRP divalent antigen-binding fragment [F(ab')2] antibody to test the hypothesis that inhibition of peripheral CGRP signaling reverses colonic hypersensitivity induced by either chronic adult stress or early life stress. A cohort of adult male rats was exposed to repeated water avoidance stress. Additionally, a second cohort consisting of female rats was exposed to a female-specific neonatal odor-attachment learning paradigm of unpredictable early life stress. Colonic sensitivity was then assessed in adult animals via behavioral responses to colorectal distension (CRD). To analyze spinal nociceptive signaling in response to CRD, dorsal horn extracellular signal-regulated kinase (ERK) 1/2 phosphorylation was measured via immunohistochemistry. Repeated psychologic stress in adulthood or unpredictable stress in early life induced colonic hypersensitivity and enhanced evoked ERK1/2 phosphorylation in the spinal cord after CRD in rats. These phenotypes were reversed by administration of a monoclonal anti-CGRP F(ab')2 fragment antibody. Stress-induced changes in visceral sensitivity and spinal nociceptive signaling were reversed by inhibition of peripheral CGRP signaling, which suggests a prominent role for CGRP in central sensitization and the development of stress-induced visceral hypersensitivity. SIGNIFICANCE STATEMENT: Targeting peripheral calcitonin gene-related peptide (CGRP) with a monoclonal anti-CGRP divalent antigen-binding fragment antibody reduced central sensitization and attenuated colonic hypersensitivity induced by either chronic adult stress or early life stress. CGRP-targeting antibodies are approved for migraine prevention, and the results of this study suggest that targeting CGRP may provide a novel treatment strategy for irritable bowel syndrome-related, stress-induced visceral pain.
Highlights
Irritable bowel syndrome (IBS) is a common brain-gut disorder estimated to affect 10%–20% of the North American population
To reduce possible immunomodulatory effects of the fragment crystallizable (Fc) region of the full-length antibody in the tested animal models, F(ab0)2 fragment antibody was used as an experimental tool to determine the specific effect of peripheral calcitonin gene-related peptide (CGRP) inhibition
We demonstrated that 24 hours after the final stress procedure induced by water avoidance, there was a significant increase in a visceromotor response (VMR) to colorectal distension (CRD) quantified as the number of abdominal contractions during the distention period when compared with SHAMtreated animals (F[3, 64] 5 108.3, P < 0.0001) (Fig. 2A)
Summary
Irritable bowel syndrome (IBS) is a common brain-gut disorder estimated to affect 10%–20% of the North American population. IBS features a constellation of clinical symptoms, including abdominal pain and discomfort, bloating, and abnormal bowel habits (Saito et al, 2002; Longstreth, 2005, 2006). The etiology of this disorder remains unclear, evidence suggests that stress is a trigger for the development of IBS symptomatology. Clinical studies have demonstrated that patients with IBS frequently report high levels of lifetime stress, which correlates with worsening of symptoms (Prusator et al, 2016). Life stress (ELS) has been implicated as a potential risk factor for IBS, with a. K.M., J.S., and S.S. are full-time employees of Teva Pharmaceutical Industries, Ltd
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