Background and Aims: Intestinal mast cell activity is modulated by the central nervous system, but the mechanisms are not well established. The aim of this study was to investigate whether cerebral thyrotropin-releasing hormone (TRH) activates intestinal mast cells and to elucidate the mechanisms involved, specifically, the contribution of mast cells to vagally stimulated luminal protein release. Methods: In anesthetized rats, mast cell activation was assessed by measuring the release of the specific mucosal rat mast cell protease II (RMCP II) and prostaglandin (PG) D2 into the intestinal lumen. Luminal protein release was measured as an index of epithelial permeability to macromolecules. Results: Intracisternal injection of the TRH analogue RX 77368 (30 ng) induced a transient increase in intestinal release of RMCP II and PGD2 that was abolished by doxantrazole. RX 77368-stimulated RMCP II release was also abolished by vagotomy and reduced by atropine by 65%. However, both systemic capsaicin and indomethacin enhanced RMCP II release. RX 77368-stimulated luminal protein release was abolished by vagotomy and reduced by doxantrazole. Conclusions: Central vagal activation by TRH stimulates intestinal mast cell secretion, in part via peripheral muscarinic receptors, and is modulated by PGs and capsaicin-sensitive afferent innervation. Intestinal mast cell activation contributes to the TRH analogue- stimulated luminal protein release.