Intrarectal Antagonism of Calcitonin Gene-Related Peptide Prevents Spinal Cord Injury-Associated Neurogenic Bowel Phenotypes

Abstract

Neurogenic bowel (NB) affects roughly 60% of people with a spinal cord injury (SCI), and these patients present with slow colonic transit, constipation, and chronic abdominal pain. The mechanisms by which NB bowel develops are unclear, thereby limiting interventions to being primarily symptom-focused and ineffective. Therefore, the main goal of this study was to identify the mechanisms that initiate and maintain NB after SCI as a critical step to develop evidence-based, novel therapeutic options to prevent NB. In previous studies, the neurogenic inflammatory mediator calcitonin gene-related peptide (CGRP) was identified as a high-priority candidate gene. Therefore, in a midthoracic rodent spinal contusion model that presents with clinically translatable NB-like phenotypes, we conducted intrarectal antagonism of CGRP activity using CGRP_8–37 (compared to vehicle administration) in mice with SCI. This was followed by histological, molecular, and functional (Ca²⁺ imaging) approaches to assess the prevention of previously reported phenotypes of NB. CGRP_8–37 significantly prevented colonic dysmotility and structural defects of the colon (i.e., expanded lymphoid nodules). There was also a prevention of microbial invasion into the colon wall and neuronal hyperresponsiveness to autologous fecal supernatants. These data support the role of CGRP/CGRP as a candidate mechanism for NB after SCI and highlight the potential for novel therapeutic treatments for the prevention of NB.