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Intravenous (iv) injection of secretin activates neurons in brain areas controlling autonomic function and emotion. Peripheral administration of secretin inhibits gastric functions through a central mechanism that is mediated by vagal dependant pathways. We investigated whether the vagus nerve is involved in intraperitoneal (ip) injection of secretin-induced brain neuronal activation in conscious rats as monitored by Fos immunohistochemistry. Secretin (40 or 100 microgram/kg, ip, -90 min) induced a linear dose-related increase in the number of Fos positive neurons in the central nucleus of the amygdala (CeA), and a plateau Fos response in the area postrema (AP), nucleus tractus solitarii (NTS), locus coeruleus (LC), Barrington's nucleus (Bar), external lateral subnucleus of parabrachial nucleus (PBel) and arcuate nucleus (Arc), and at the highest dose, in the dorsal motor nucleus of the vagus (DMV) compared with ip injection of vehicle. Double immunohistochemistry in the NTS showed that a substantial number of neurons activated by secretin (40 microgram/kg, ip) are tyrosine hydroxylase positive. Subdiaphragmatic vagotomy (-7 days) abolished Fos expression-induced by ip secretin (40 microgram/kg) in the NTS, DMV, LC, Bar, PBel and CeA, while a significant rise in the AP was maintained. In contrast, capsaicin (-10 days) did not influence the Fos induction in the above nuclei. Quantitative real-time polymerase chain reaction (PCR) and reverse transcription PCR showed that secretin receptor mRNA is expressed in the nodose ganglia and levels were higher in the right compared to the left ganglion. These results indicate that peripheral secretin activates catecholaminergic NTS neurons as well as neurons in pontine and limbic nuclei regulating autonomic functions and emotion through vagal dependent capsaicin resistant pathways. Secretin injected ip may signal to the brain by interacting with secretin receptors on vagal afferent as well as on AP neurons outside the blood brain barrier.