Martínez V, Rivier J, Coy D, Taché Y
CURE: Digestive Diseases Research Center, VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA.
J Pharmacol Exp Ther. 2000 Jun;293(3):1099-105.
We previously showed that the somatostatin receptor 5 (sst(5))-preferring agonist BIM-23052 injected intracisternally (i.c. ; 0.8 nmol/rat) stimulated gastric emptying of a non-nutrient meal in conscious rats. In this study, we investigated the neural pathways and specificity of BIM-23052 action. BIM-23052 (0.4, 0.8, and 1.2 nmol/rat i.c.) stimulated gastric transit; values of gastric emptying were 65.5 +/- 6.5, 77.4 +/- 5.3, and 77.7 +/- 1.9%, respectively, compared with 43.2 +/-3.2% in i.c. saline group. Intravenous injection of BIM-23052 (0.8 nmol/rat) had no effect. BIM-23052 (0.8 nmol/rat i.c.) action was prevented by subdiaphragmatic vagotomy or atropine. Medullary thyrotropin-releasing hormone (TRH) is known to play a physiological role in the vagal stimulation of gastric motor function. TRH receptor antisense oligodeoxynucleotides injected i.c. with a regimen that prevented TRH (0.3 nmol/rat i.c.)-induced enhanced gastric emptying did not influence BIM-23052 stimulatory action. Somatostatin-28 (0.2-1.2 nmol/rat i.c.), which possesses a higher affinity than somatostatin-14 for sst(5), and the cyclic octapeptide des-AA(1,2,4,5,12,13)[D-Trp(8)]somatostatin (0.2-1.2 nmol/rat i.c.), an oligo-somatostatin analog that shares similar brain actions as somatostatin-28, induced a dose-related stimulation of gastric emptying. Somatostatin-14 and the preferring peptide agonists for sst(1), CH-275; sst(2), DC-32-87; sst(3), BIM-23056 and L-796,778; and sst(4), L-803,087 had no significant effect on gastric emptying when injected i.c. at 0.8 nmol/rat. These results show that BIM-23056 injected i.c. acts in the brain independently from medullary TRH to induce a vagal cholinergic stimulation of gastric emptying through the sst(5) receptor subtype.
我们之前的研究表明，向清醒大鼠脑池内注射（i.c.；0.8 nmol/大鼠）偏爱生长抑素受体5（sst(5)）的激动剂BIM-23052，可刺激非营养性食物的胃排空。在本研究中，我们探究了BIM-23052作用的神经通路及特异性。BIM-23052（0.4、0.8和1.2 nmol/大鼠i.c.）可刺激胃转运；胃排空值分别为65.5±6.5%、77.4±5.3%和77.7±1.9%，而脑池内注射生理盐水组的胃排空值为43.2±3.2%。静脉注射BIM-23052（0.8 nmol/大鼠）无作用。膈下迷走神经切断术或阿托品可阻断BIM-23052（0.8 nmol/大鼠i.c.）的作用。已知延髓促甲状腺激素释放激素（TRH）在迷走神经刺激胃运动功能中发挥生理作用。脑池内注射TRH受体反义寡脱氧核苷酸，其给药方案可阻断TRH（0.3 nmol/大鼠i.c.）诱导的胃排空增强，但不影响BIM-23052的刺激作用。生长抑素-28（0.2 - 1.2 nmol/大鼠i.c.）对sst(5)的亲和力高于生长抑素-14，以及环八肽des-AA(1,2,4,5,12,13)[D-Trp(8)]生长抑素（0.2 - 1.2 nmol/大鼠i.c.），一种与生长抑素-28具有相似脑内作用的寡聚生长抑素类似物，均可诱导剂量相关的胃排空刺激。当以0.8 nmol/大鼠的剂量脑池内注射时，生长抑素-14以及sst(1)的偏爱肽激动剂CH-275；sst(2)的DC-32-87；sst(3)的BIM-23056和L-796,778；sst(4)的L-803,087对胃排空均无显著影响。这些结果表明，脑池内注射的BIM-23056在脑内独立于延髓TRH发挥作用，通过sst(5)受体亚型诱导迷走神经胆碱能刺激胃排空。
