Wan Shuxia, Coleman F Holly, Travagli R Alberto
Department of Neuroscience, Pennington Biomedical Research Center-Louisiana State University System, 6400 Perkins Rd., Baton Rouge, LA 70808, USA.
Am J Physiol Gastrointest Liver Physiol. 2007 Aug;293(2):G484-92. doi: 10.1152/ajpgi.00116.2007. Epub 2007 Jun 14.
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.
已知胆囊收缩素（CCK）以旁分泌方式通过迷走神经回路增加胰腺外分泌。然而，最近的证据表明，CCK - 8s的作用不仅限于迷走神经传入纤维，还直接影响脑干结构。在脑干内，迷走神经背运动核（DMV）的节前神经元向包括胰腺在内的膈下内脏发送传出纤维。我们的目的是研究DMV神经元是否对外源性应用的CCK - 8s有反应，如果有反应，其作用机制是什么。使用全细胞膜片钳记录，我们发现用CCK - 8s灌注可在约60%已鉴定的投射到胰腺的DMV神经元中诱导浓度依赖性兴奋。河豚毒素可显著降低这种去极化，提示其既有直接作用（作用于DMV膜）也有间接作用（作用于局部突触回路）。实际上，CCK - 8s增加了DMV神经元上微小兴奋性电流的频率。CCK - A拮抗剂洛谷胺可阻止CCK - 8s介导的兴奋，而CCK - B选择性激动剂非硫酸化CCK则无作用，提示仅涉及CCK - A受体。在电压钳实验中，CCK - 8s诱导的内向电流在 - 106±3 mV时反转，输入电阻增加150±15%，提示该作用由钾电导关闭介导。实际上，CCK - 8s降低了钙依赖性钾电导的幅度和衰减时间常数。当用胰多肽（其可减少胰腺外分泌）进行测试时，对CCK - 8s产生兴奋反应的细胞反而被胰多肽抑制。这些数据表明，CCK - 8s也可能通过对投射到胰腺的DMV神经元的作用来控制胰腺外分泌。
