Decreases in mucosally‐evoked tachykinin signaling pathways can explain age‐related reductions in murine colonic motility patterns

• Published in: Neurogastroenterology and motility 2024-11, Vol.36 (11), p.e14891-n/a
• Main Authors: Yeoman, Mark S., Fidalgo, Sara, Hobby, India, Hafeez, Ali, Ranson, Rachel N., Saffrey, M. Jill, Patel, Bhavik Anil
• Format: Article
• Language: English
• Subjects: Age; Aging; Aging - physiology; Animals; Colon; Colon - drug effects; Colon - metabolism; colonic transit; Constipation; Gastrointestinal Motility - drug effects; Gastrointestinal Motility - physiology; Intestinal Mucosa - drug effects; Intestinal Mucosa - metabolism; Male; Mice; Mice, Inbred C57BL; Motility; Mucosa; Myoelectric Complex, Migrating - drug effects; Myoelectric Complex, Migrating - physiology; Neurokinin A; Neurokinin NK2 receptors; Phenotypes; Reflexes; Signal Transduction - drug effects; Signal Transduction - physiology; Smooth muscle; Tachykinin; Tachykinin receptors; Tachykinins - metabolism
• ISSN: 1350-1925; 1365-2982; 1365-2982
• DOI: 10.1111/nmo.14891

Background Increasing age increases the incidence of chronic constipation and fecal impaction. The contribution of the natural aging process to this phenotype is unclear. This study explored the effects of age on key motility patterns in the murine colon and determined the contribution that altered neurokinin 2 (NK2) ‐mediated signaling made to the aging phenotype. Methods Mucosal reflexes, colonic migrating motor complexes (CMMCs) and colonic motility assays were explored in isolated ex vivo colons from 3, 12–14, 18‐ and 24‐months old mice and the NK2‐mediated response determined. Electrical field stimulation (EFS) or exogenous drug application were used to explore the role of the mucosa in colonic segments. Key Results Aging reduced the force of contraction of the distal colon mucosal reflex, the frequency and force of contraction of CMMCs and the NK2‐mediated component of both motility patterns. Ondansetron, a 5‐HT3 receptor antagonist, blocked a component of both motility patterns in full thickness but not in mucosa‐free segments of the distal colon. 5, hydroxytryptamine (5‐HT) and EFS‐evoked NK2‐dependent contractions were reduced with increasing age. Smooth muscle sensitivity to 5‐HT or neurokinin A (NKA) was not altered with age. In isolated colon motility assays application of NKA decreased transit time in 24‐months colon and the NK2 antagonist GR159897 increased transit times in both 3‐ and 24‐months old colons. Conclusions and Inferences Aging impairs key motility patterns in the murine colon. These changes involve a decrease in mucosally‐evoked NK2‐mediated signaling. Targeting NK2‐mediated signaling may provide a novel approach to treating age‐related motility disorders in the lower bowel. The natural aging process can reduce lower bowel motility, leading to an increased incidence of chronic constipation. Aging reduces tachykinin signaling in the distal colon reducing colonic motility. Medicines that increase tachykinin signaling could be useful for treating chronic constipation in older people.