The central nervous system effects of thyrotropin-releasing hormone (TRH) and calcitonin gene-related peptide (CGRP) on exocrine pancreatic secretion were studied in freely moving rats. TRH (0.05-0.5 nmol) significantly stimulated, whereas CGRP (0.1-1.0 nmol) significantly inhibited, volume, protein, and bicarbonate secretion. Pretreatment of the animals with the ganglionic blocking agent chlorisondamine abolished the pancreatic responses produced by both peptides. In contrast, vagotomy abolished the stimulatory effect of TRH, whereas noradrenergic blockade with bretylium or phentolamine abolished the inhibitory effect of CGRP. Atropine significantly attenuated, but the vasoactive intestinal peptide (VIP) antagonist [D-p-Cl-Phe6, Leu17]VIP completely abolished the stimulatory effect of TRH. Pancreatic secretory responses stimulated by cerebral TRH or by peripheral VIP were inhibited dose dependently by peripheral [D-p-Cl-Phe6,Leu17]VIP. Inhibition of pancreatic secretion induced by cerebral CGRP or by peripheral norepinephrine was prevented by intravenous phentolamine. These results indicate 1) cerebral TRH stimulates and cerebral CGRP inhibits exocrine pancreatic secretion in freely moving rats; 2) the effects of TRH are mediated by vagal efferents, and the primary peripheral transmitter appears to be VIP acting on VIP receptors, whereas muscarinic efferents are less important; and 3) the effects of CGRP are mediated by sympathetic noradrenergic efferents via alpha-adrenergic receptors.