Supraspinal neurotensin-induced antianalgesia in mice is mediated by spinal cholecystokinin.
Intracerebral injection of neurotensin into specific brain loci in rats produces hyperalgesia due to the release of cholecystokinin (CCK) in the spinal cord. The present purpose was to show in another species that neurotensin can antagonize the antinociceptive action of morphine through the spinal CCK mechanism in mice. Neurotensin given intracerebroventricularly (i.c.v.) at doses higher than 100 ng produced antinociception in the tail flick test. However, at lower doses between 1 pg to 25 ng, neurotensin antagonized the antinociceptive action of morphine given intrathecally (i.t.), thus demonstrating the antianalgesic activity of neurotensin. The rightward shift in the morphine dose-response curve produced by i.c.v. neurotensin was eliminated by an i.t. pretreatment with CCK8 antibody (5 microl of antiserum solution diluted 1:1000). I.t. administration of lorglumide, a CCK(A)-receptor antagonist (10-1000 ng), and PD135,158, a CCK(B)-receptor antagonist (250-500 ng), also eliminated the antianalgesic action of neurotensin. Thus, the mechanism of the antianalgesic action of neurotensin given i.c.v. involved spinal CCK. This mode of action is similar to that for the antianalgesic action of supraspinal pentobarbital which also involves spinal CCK. (+info
Inhibition of food intake in response to intestinal lipid is mediated by cholecystokinin in humans.
Intraduodenal fat inhibits gastric emptying and exerts early satiation in animals and humans, but it is not clear whether the effects are mediated by cholecystokinin (CCK) in humans. Here, we tested whether CCK-A receptors mediate the inhibition of fat on food intake. Two sequential, double-blind, crossover studies were performed in 24 male subjects. First, subjects received either intraduodenal fat or saline together with a preload of either water or banana shake. Second, 12 subjects received either intraduodenal fat or saline perfusion plus a concomitant infusion of saline or loxiglumide, a specific CCK-A receptor antagonist, together with a preload of banana shake. In both studies, subjects were free to eat and drink as much as they wished. Fat induced a reduction in calorie intake (P < 0.05) compared with controls. Furthermore, a decrease in hunger feelings was observed. Infusion of loxiglumide abolished the effects of fat. Duodenal fat interacts with an appetizer to modulate energy intake in humans. This effect is mediated by CCK-A receptors. (+info
Effects of spinal cholecystokinin receptor antagonists on morphine antinociception in a model of visceral pain in the rat.
The objective of the present study was to determine the effects of spinal cholecystokinin (CCK) receptor antagonists on morphine antinociception in a model of visceral nociception, colorectal distension, in rats with chronic colonic inflammation and vehicle-treated controls. Three to five days after intracolonic instillation of 2,4,6-trinitrobenzenesulfonic acid (TNBS), an enhanced visceromotor response to all pressures of colorectal distension (10-80 mm Hg) was evident. The ED(50) of intrathecal morphine (0.93 microgram) in vehicle-treated rats produced significantly greater antinociception in TNBS-treated rats. Intrathecal proglumide, a nonselective CCK receptor antagonist, dose dependently enhanced the antinociceptive effect of morphine in vehicle-treated rats, but not in TNBS-treated rats. Similarly, L-365, 260, a specific CCK(B) receptor antagonist, dose dependently increased morphine's antinociceptive effects in vehicle-treated rats but had no effect in rats with TNBS-induced colonic inflammation. L-364,718, a specific CCK(A) receptor antagonist, had no effect on morphine antinociception in either vehicle-treated or TNBS-treated rats. These data indicate that CCK, acting at the CCK(B) receptor, is involved in modulating morphine antinociception following a noxious visceral stimulus. However, CCK receptor antagonists no longer enhance morphine antinociception after instillation of intracolonic TNBS, suggesting that visceral inflammation may lead to a reduction in spinal CCK release. (+info
The role of long chain fatty acids in regulating food intake and cholecystokinin release in humans.
BACKGROUND AND AIMS: The mechanism of intraduodenal fat induced inhibition of food intake is still unclear. Therefore, we tested the ability of duodenal fatty acids to suppress food intake at a lunchtime meal; in addition, we were interested to test if these effects were mediated by cholecystokinin (CCK) A receptors. SUBJECTS AND METHODS: Three sequential double blind, three period crossover studies were performed in 12 healthy males each: (1) subjects received intraduodenal fat with or without 120 mg of tetrahydrolipstatin, an inhibitor of gastrointestinal lipases, or saline; (2) volunteers received intraduodenal long chain fatty acids, medium chain fatty acids, or saline; (3) subjects received long chain fatty acids or saline together with concomitant intravenous infusions of saline or loxiglumide, a specific CCK-A receptor antagonist. The effect of these treatments on food intake and feelings of hunger was quantified. RESULTS: Intraduodenal fat perfusion significantly (p<0.05) reduced calorie intake. Inhibition of fat hydrolysis abolished this effect. Only long chain fatty acids significantly (p<0.05) decreased calorie intake, whereas medium chain fatty acids were ineffective. Infusion of loxiglumide abolished the effect of long chain fatty acids. CONCLUSIONS: Generation of long chain fatty acids through hydrolysis of fat is a critical step for fat induced inhibition of food intake; the signal is mediated via CCK-A receptors. (+info
Role of cholecystokinin in the intestinal phase of pancreatic circulation in dogs.
The regulatory mechanisms of postprandial pancreatic hyperemia are not well characterized. The aim of this study is to clarify the role of cholecystokinin (CCK) in the intestinal phase of pancreatic circulation. Pancreatic, gastric, and intestinal blood flows were measured by ultrasound transit-time blood flowmeters in five conscious dogs. Pancreatic and gastric secretion and blood pressure were also monitored. Synthetic CCK octapeptide (CCK-8) or gastrin heptadecapeptide (gastrin-17) was infused intravenously, and milk was infused into the duodenum with or without loxiglumide, a specific CCK-A receptor antagonist. CCK-8 induced dose-related increases of pancreatic, but not gastric or intestinal, blood flow and protein secretion without affecting systemic blood pressure. Gastrin-17 did not affect pancreatic blood flow. An intraduodenal infusion of milk increased pancreatic and intestinal blood flows and pancreatic protein secretion. Loxiglumide completely inhibited pancreatic blood flow and protein responses to CCK-8 and milk but not the intestinal blood flow response. CCK is a potent and specific pancreatic vasodilator, with its effect mediated by CCK-A receptors. CCK plays an important role in the regulation of the intestinal phase of the pancreatic circulation in dogs. (+info
Effects of proglumide, a gastrin receptor antagonist, on human large intestine carcinoma SW480 cell line.
OBJECTIVE: To explore the effects of proglumide, a gastrin receptor antagonist, on the amount of viable cells, synthesis of DNA and protein, and cell proliferation cycle in human large intestine carcinoma SW480 cell line in order to provide experimental basis for treatment of large intestine carcinoma using proglumide. METHODS: Large intestine carcinoma SW480 cells at logarithmic growth stage were cultivated with different concentrations of proglumide for different periods of time, then the amount of viable cells was determined by MTT colorimetric analysis. The SW480 cells were cultivated with proglumide, pentagastrin, proglumide + pentagastrin for the same period of time, then the contents of DNA and protein and the cell proliferation cycle were determined by flow-cytometry. RESULTS: The amount of viable cells, synthesis of DNA and protein, distribution of cell cycle, and proliferation index (PI) in the proglumide group did not differ significantly from those in the pentagastrin group (P > 0.05). The amount of viable cells in the pentagastrin group was significantly higher than that in the pentagastrin group (P < 0.01). In the proglumide + pentagastrin group the amount of viable cells, synthesis of DNA and protein, amount of S and G2M phase cells, and PI were all significantly lower than those in the pentagastrin group (all P < 0.01), and the amount of G0/G1 phase cells was significantly higher than that in the pentagastrin group (P < 0.01), but none of the above differed from those in the control group (all P > 0.05). CONCLUSIONS: Proglumide has no obvious effect on the growth of human large intestine carcinoma SW480 cell line, but can inhibit the growth-promoting effect of pentagastrin on large intestine carcinoma cells. The mechanism may be that proglumide inhibits the promoting effect of pentagastrin on the synthesis of DNA and protein of carcinoma cells, and then inhibits carcinoma cell growth from G0/G1 phase to S and G2M phase. (+info
The effect of cholecystokinin antagonism on postprandial lower oesophageal sphincter function in asymptomatic volunteers and patients with reflux disease.
BACKGROUND: Postprandial acid reflux is thought to be mediated by the increase in transient lower oesophageal sphincter relaxations (TLOSR) frequency and fall in lower oesophageal sphincter (LOS) pressure seen after ingestion of a meal. Studies in animals and healthy volunteers suggest that cholecystokinin (CCK) may play a role. AIM: To study the role of CCK in postprandial LOS function using the CCK antagonist loxiglumide. SUBJECTS: 10 asymptomatic volunteers (7 male, 20-29 years) and 9 patients with symptomatic gastro-oesophageal reflux (4 male, 33-66 years). METHODS: Oesophageal, LOS and gastric pressure and oesophageal pH readings were recorded for 1 h before and 2 h after intragastric infusion of a 200 kCal, 300 mL long chain triglyceride meal. Each subject underwent two studies and received intravenous loxiglumide or placebo infusion in randomized order. RESULTS: During placebo infusion, postprandial LOS pressure fell [volunteers: 17 (9-31) to 7 (1-19) mmHg (P < 0.01), patients: 15 (6-26) to 9 (2-21) mmHg (P=0.02)] and TLOSR frequency increased [volunteers: 0 (0-1) to 2 (0-7) per hour (P=0.01), patients: 0 (0-3) to 2 (0-10) per hour (P=0.03)]. Loxiglumide infusion attenuated the postprandial fall in LOS pressure and the postprandial increase in TLOSR frequency [volunteers: 0 (0-3) per hour (P=0.04 vs. placebo), patients: 0 (0-2) per hour (P=0.03 vs. placebo)], but it had only modest effects on postprandial acid exposure [volunteers: placebo 45 (0-1725) vs. loxiglumide 0 (0-443) seconds (N.S.), patients: placebo 60 (0-3442) seconds vs. loxiglumide 31 (0-1472) seconds (N.S.)]. CONCLUSIONS: Loxiglumide inhibits TLOSR and attenuates the fall in LOS pressure following a meal, but has only modest effects on postprandial gastro-oesophageal acid reflux. (+info
Opioid and cholecystokinin antagonists alleviate gastric inhibition of food intake by premeal loads of casein in meal-fed rats.
This study was undertaken to determine whether casein, compared with its constituent amino acids, given at the onset of a meal, would influence intake due to cholecystokinin (CCK) or opioid activity. Male Sprague-Dawley rats (n = 80; 225 g) were given either premeal loads of casein or its constituent amino acids and treated with opioid or CCK antagonists in a 2 x 4 factorially designed experiment. During a 21-d period, rats were meal-fed by restricting access to food to 5 h/d. The rats were fed the AIN-93 diet with soy isolate substituted for casein as the dietary protein source. On d 7-21, rats were given oral premeal loads of 5 mL of a 50 g/L casein or constituent amino acid solution before meal-feeding. On d 14-21, 20 rats were injected intraperitoneally with one of the following treatments: saline, naltrexone (l mg/kg), naloxone methiodide (5 mg/kg) or lorglumide (1 mg/kg) before the premeal load and feeding. Antagonist treatments increased intake (P < 0.05) by 15.3% compared with saline treatment (7.82 vs. 9.02 g/d) in rats given premeal loads of casein. Intake of rats given premeal loads of amino acids was not influenced by antagonists. At 2 h after feeding on d 21, the rats were killed, bled and eviscerated. Effects of antagonists on stomach and intestinal mass, digesta contents and fecal output were also dependent on the type of premeal load, indicating that gastric retention of digesta due to casein was mediated by CCK and opioids. Body weight accretion, liver, and epididymal fat mass and blood concentrations of specific amino acids changed in the same manner as intake (P < 0.05). Serum insulin was greater (P < 0.05) in casein-treated rats and reduced (P < 0.01) by opioid antagonists. Satiety associated with premeal loads of casein is related to changes in gastrointestinal function of meal-fed animals and involves both opioid and CCK regulation. (+info