Cholecystokinin-8s excites identified rat pancreatic-projecting vagal motoneurons.
It is known that cholecystokinin (CCK) acts in a paracrine fashion to increase pancreatic exocrine secretion via vagal circuits. Recent evidence, however, suggests that CCK-8s actions are not restricted to afferent vagal fibers, but also affect brain stem structures directly. Within the brain stem, preganglionic neurons of the dorsal motor nucleus of the vagus (DMV) send efferent fibers to subdiaphragmatic viscera, including the pancreas. Our aims were to investigate whether DMV neurons responded to exogenously applied CCK-8s and, if so, the mechanism of action. Using whole cell patch-clamp recordings we show that perfusion with CCK-8s induced a concentration-dependent excitation in approximately 60% of identified pancreas-projecting DMV neurons. The depolarization was significantly reduced by tetrodotoxin, suggesting both direct (on the DMV membrane) and indirect (on local synaptic circuits) effects. Indeed, CCK-8s increased the frequency of miniature excitatory currents onto DMV neurons. The CCK-A antagonist, lorglumide, prevented the CCK-8s-mediated excitation whereas the CCK-B preferring agonist, CCK-nonsulfated, had no effect, suggesting the involvement of CCK-A receptors only. In voltage clamp, the CCK-8s-induced inward current reversed at -106 +/- 3 mV and the input resistance increased by 150 +/- 15%, suggesting an effect mediated by the closure of a potassium conductance. Indeed, CCK-8s reduced both the amplitude and the time constant of decay of a calcium-dependent potassium conductance. When tested with pancreatic polypeptide (which reduces pancreatic exocrine secretion), cells that responded to CCK-8s with an excitation were, instead, inhibited by pancreatic polypeptide. These data indicate that CCK-8s may control pancreas-exocrine secretion also via an effect on pancreas-projecting DMV neurons.
Wan
Shuxia
S
Department of Neuroscience, Pennington Biomedical Research Center-Louisiana State University System, 6400 Perkins Rd., Baton Rouge, LA 70808, USA.
Coleman
F Holly
FH
Travagli
R Alberto
RA
D000200:Action Potentials; D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001339:Autonomic Fibers, Preganglionic / Q000187:drug effects / Q000378:metabolism*; D001933:Brain Stem / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019706:Excitatory Postsynaptic Potentials; D006727:Hormone Antagonists / Q000494:pharmacology; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism*; D010179:Pancreas / Q000294:innervation* / Q000378:metabolism; D010191:Pancreatic Polypeptide / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism; D024681:Potassium Channels, Calcium-Activated / Q000378:metabolism; D011377:Proglumide / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043886:Receptor, Cholecystokinin A / Q000187:drug effects / Q000378:metabolism*; D012844:Sincalide / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D014630:Vagus Nerve / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*
C090019:8-sulfocholecystokinin octapeptide; D000779:Anesthetics, Local; D006727:Hormone Antagonists; D024681:Potassium Channels, Calcium-Activated; D043886:Receptor, Cholecystokinin A; D013779:Tetrodotoxin; D010191:Pancreatic Polypeptide; D011377:Proglumide; C048181:lorglumide; D012844:Sincalide; D011188:Potassium; D002118:Calcium