Accumulating evidence suggests that central thyrotropin-releasing hormone (TRH) administration induces gastric erosion 4 hours after administration through the vagal nerves. However, the early changes in the gastric mucosa during these 4 hours have not been described. To assess the early changes in the gastric mucosa after intracisternal injection of RX-77368, a stable TRH analogue, we measured the blood to lumen ⁵¹Cr-EDTA clearance and examined the effects of vagotomy, atropine, omeprazole, and hydrochloric acid (HCl) on RX-77368-induced mucosal permeability. A cytoprotective dose of RX-77368 (1.5 ng) did not increase mucosal permeability. However, higher doses significantly increased mucosal permeability. Permeability peaked within 20 min and gradually returned to control levels in response to a 15 ng dose (submaximal dose). Increased mucosal permeability was not recovered following a 150 ng dose (ulcerogenic dose). This increase in permeability was inhibited by vagotomy or atropine. Intragastric perfusion with HCl did not change the RX-77368 (15 ng)-induced increase in permeability, but completely inhibited the recovery of permeability after the peak. Pretreatment with omeprazole did not change the RX-77368 (15 ng)- induced increase in permeability, but quickened the recovery of permeability after the peak. These data indicate that the RX-77368-induced increase in permeability is mediated via the vagal-cholinergic pathway and is not a secondary change in RX-77368-induced acid secretion. Inhibited recovery of permeability upon exposure to an ulcerogenic RX-77368 dose or upon exposure to HCl plus a submaximal dose of RX-77368 may be crucial for the induction of gastric mucosal lesions by central RX-77368 administration.