Effects of M1 and CCK antagonists on latency of pancreatic amylase response to intestinal stimulants

In six conscious dogs with gastric and duodenal cannulas, secretin (164 pmol · kg−1 · h−1 iv) was given to provide a flow of pancreatic juice of ∼1 drop/s. Amylase activity was measured in each drop before and after rapid intravenous injection of caerulein (7.4 pmol/kg) or intraduodenal injection of l-tryptophan (1 mmol), sodium oleate (3 mmol), and HCl (3 mmol). All experiments were repeated in the presence of the M1 receptor antagonist telenzepine (81 nmol · kg−1 · h− iv) and the cholecystokinin (CCK) receptor antagonist L-364718 (0.1 mg/kg iv). Latency of amylase response (time between injection of stimulant and sustained increase in amylase activity greater than mean + 3 SD of prestimulatory activity) to tryptophan (17 ± 7 s; n = 6) and oleate (16 ± 5 s) was significantly ( P < 0.05) shorter than to caerulein (28 ± 4 s) and HCl (120 ± 47 s). Telenzepine significantly increased the latency of amylase response to tryptophan and oleate by >10-fold but not the latency to caerulein or HCl. L-364718 abolished the amylase response to all stimulants. These findings indicate that the early amylase response to intraduodenal tryptophan and oleate is mediated by a neural enteropancreatic reflex ending on M1 receptors rather than by hormone release. However, the activation of (possibly vagal) CCK receptors is essential to run the reflex. The early amylase response to intraduodenal HCl is probably mediated by the release of CCK into the blood circulation.

Pathways of Fos expression in locus ceruleus, dorsal vagal complex, and PVN in response to intestinal lipid

Exogenous cholecystokinin (CCK) injected peripherally mimics effects of lipid entering the intestine on food intake and gastric motility via vagal afferents and induces c- fos expression in the locus ceruleus complex (LCC), nucleus of the solitary tract (NTS), area postrema (AP), and paraventricular nucleus (PVN). However, the role of peripheral endogenous CCK in induction of c- fos expression in the brain at ingestion of nutrients is controversial. In awake rats, intraduodenal lipid infusion markedly increased Fos protein-like immunoreactivity (FLI) in these brain nuclei. Perivagal capsaicin pretreatment reduced the increase of FLI in the LCC, NTS, and PVN by 66–86% and in the AP by 46%. The CCK-A receptor antagonist MK-329 (0.1 mg/kg ip) diminished the FLI increase in LC, NTS, AP, and PVN by 39–100%; the CCK-B receptor antagonist L-365,260 reduced the increased FLI in the AP by 54%. After capsaicin pretreatment, both CCK antagonists had additional inhibitory effects only on FLI in the AP. These findings suggest that entry of lipid into the intestine activates c- fos in the LCC, NTS, and PVN predominantly via CCK-A receptors on vagal afferents and in the AP via vagal and nonvagal pathways, as well as CCK-B and CCK-A receptors.

Cholecystokinin Type A and Type B Receptors and Their Modulation of Opioid Analgesia

Several lines of evidence indicate that cholecystokinin (CCK) antagonists potentiate analgesia induced by exogenous opioids. Similarly, CCK antagonists enhance analgesia induced by procedures that activate endogenous opioid systems. However, because there are substantial species differences in receptor specificity and distribution, the role of CCK type A and type B receptors has yet to be clearly established.