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Pubmed-A MONOCLONAL ANTI-CGRP ANTIBODY DECREASES STRESS-INDUCED COLONIC HYPERSENSITIVITY


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J Pharmacol Exp Ther. 2021 Oct 7:JPET-AR-2021-000731. doi: 10.1124/jpet.121.000731. Online ahead of print.

ABSTRACT

BACKGROUND: Irritable bowel syndrome (IBS) is a brain-gut disorder characterized by abdominal pain and altered bowel habits. While 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 utilize a monoclonal anti-CGRP F(ab')2 fragment antibody to test the hypothesis that inhibition of peripheral CGRP signaling reverses colonic hypersensitivity induced by either chronic adult stress or early life stress. METHODS: A cohort of adult male rats were exposed to repeated water avoidance stress (WAS). Additionally, a second cohort consisting of female rats were exposed to a female-specific neonatal odor-attachment learning paradigm of unpredictable early life stress (ELS). Colonic sensitivity was then assessed in adult animals via behavioral responses to colorectal distension (CRD). In order to analyze spinal nociceptive signaling in response to CRD, dorsal horn extracellular signal-regulated kinase (ERK1/2) phosphorylation (pERK), was measured via immunohistochemistry. RESULTS: Repeated psychological stress in adulthood or unpredictable stress in early life induced colonic hypersensitivity and enhanced evoked ERK1/2 phosphorylation in the spinal cord following CRD in rats. These phenotypes were reversed by administration of a monoclonal anti-CGRP F(ab')2 fragment antibody. CONCLUSIONS: Stress-induced changes in visceral sensitivity and spinal nociceptive signaling were reversed by inhibition of peripheral CGRP signaling, suggesting a prominent role for CGRP in central sensitization and the development of stress-induced visceral hypersensitivity. Significance Statement Targeting peripheral CGRP with a monoclonal anti-CGRP F(ab')2 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 our results suggest that targeting CGRP may provide a novel treatment strategy for IBS-related stress-induced visceral pain.

PMID:34620725 | DOI:10.1124/jpet.121.000731

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