Galanin signaling in stress-induced brain-gut axis dysregulation: Receptor-specific mechanisms and context-dependent pharmacology.

Stress-related dysregulation of the brain-gut axis may help explain the frequent co-occurrence of gastrointestinal disorders and neuropsychiatric phenotypes, including anxiety and depression. Acute and chronic stress can alter gastrointestinal motility, visceral sensation, mucosal barrier integrity, and central affective circuits through the hypothalamic-pituitary-adrenal (HPA) axis, the autonomic nervous system (ANS), immune and inflammatory signaling, and changes in gut microbial ecology. Galanin is distributed across central stress-related nuclei, the enteric nervous system, visceral afferent pathways, and mucosal immune cells, positioning the galanin system as a potential integrator of bidirectional brain-gut signaling. This review examines the expression, receptor biology, and regulatory actions of galanin and its three receptors-galanin receptor 1 (GalR1), galanin receptor 2 (GalR2), and galanin receptor 3 (GalR3)-in stress-induced brain-gut axis dysregulation, while galanin-like peptide (GALP) and spexin provide additional endogenous-ligand context for interpreting GalR pharmacology. The galanin system is neither uniformly protective nor uniformly detrimental. Its functional effects depend on ligand identity, receptor subtype, cell type, anatomical site, stress stage, and inflammatory state, as well as receptor complexes and downstream signaling bias. This context-dependent framework may help identify settings in which galanin-pathway modulation is most mechanistically plausible according to stress stage, inflammatory status, visceral sensitivity, and barrier function. Future studies should prioritize subtype-directed, tissue-restricted, and signaling-biased strategies while maintaining a clear distinction between experimental pharmacological utility, preclinical therapeutic potential, and clinical applicability.