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PubMed2001

Inhibition of the preferential binding of actin to the N-terminal hydratase domain of the 78-kDa gastrin-binding protein by non-steroidal anti-inflammatory drugs and gastrin receptor antagonists.

The 78 kDa gastrin-binding protein (GBP) is a likely target for the antiproliferative effects of gastrin receptor antagonists and non-steroidal anti-inflammatory drugs (NSAIDs) on colorectal carcinoma cells (Baldwin GS, Murphy VJ, Yang Z, and Hashimoto T. J Pharmacol Exp Ther 1998;286:1110-14). This study tested the hypotheses that the GBP bound actin, and that the interaction could be disrupted by gastrin receptor antagonists and NSAIDs. Binding of actin to the GBP was assessed by competition with (125)I-[Nle(15)]-gastrin(2,17) in a covalent cross-linking assay, and by comparison of (125)I-actin binding to the N- and C-terminal GBP domains, which had been expressed independently in E. coli as glutathione-S-transferase (GST) fusion proteins. The ability of gastrin receptor antagonists and NSAIDs to interfere with the actin-GBP interaction was measured by release of (125)I-actin from preformed complexes with the N- and C-terminal domain-GST fusion proteins. Actin purified from skeletal muscle or from gastric mucosal cytosol competed with (125)I-[Nle(15)]-gastrin(2,17) for binding to the GBP with IC(50) values of 2.6 +/- 0.7 microM, and 2.1 +/- 0.7 microM, respectively. The amount of (125)I-actin from either source bound to the N-terminal GBP domain was 8.2 times greater than the amount bound to the C-terminal domain. Binding of actin to both domains was inhibited by the gastrin receptor antagonists proglumide and benzotript, and by NSAIDs. We conclude that the GBP may associate with the cytoskeleton via an interaction between its N-terminal domain and actin, and that the association may be disrupted either by gastrin receptor antagonists or by NSAIDs.

Actins↗
PubMed2000

Affinity of cholecystokinin receptor antagonists for the gastrin-binding protein.

A 78 kDa gastrin-binding protein is a likely target for the anti-proliferative effects of the cholecystokinin (CCK) receptor antagonists D,L-4-benzamido-N,N-dipropylglutaramic acid (proglumide) and N-4-chlorobenzoyl-L-tryptophan (benzotript) on colorectal carcinoma cell lines [Baldwin, G.S., 1994. Antiproliferative gastrin/cholecystokinin receptor antagonists target the 78-kDa gastrin-binding protein. Proc. Natl. Acad. Sci. USA 91, 7593-7597.]. Definition of the physiological role of the gastrin-binding protein has been hampered by the very low affinity of benzotript for the gastrin-binding protein. Benzotript analogues were therefore tested for their ability to inhibit the binding of iodinated gastrin to the gastrin-binding protein. The affinity of the most potent analogue (the D-isomer of benzotript, CR 665) was similar to the value reported previously for the L-isomer. In order to isolate more potent binding inhibitors, several selective CCK receptor antagonists were also tested as inhibitors of the binding of gastrin to the gastrin-binding protein. The affinity of the most potent binding inhibitor PD 149164 (benzenebutanoic acid, 4-fluoro-!b/-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo-[3.3 .1. 1(3,7)]dec-2-yloxy)carbonyl]amino]propyl]amino]-, [R-(R*,S*)]-) was approximately 10-fold higher than the L-isomer of benzotript. PD 149164 may serve as the lead compound for the future development of more potent and selective gastrin-binding protein inhibitors.

Adamantane↗
PubMed1991

Early acinar cell changes in caerulein-induced interstitial acute pancreatitis in the rat.

Early ultrastructural and immunohistochemical changes caused by supramaximal secretory stimulation with caerulein were studied in the rat pancreas. The morphological basis for the earlier reported decrease of pancreatic juice secretion after supramaximal caerulein was the appearance of swollen and irregular zymogen-like material containing structures with short segments of budding bristle-coated membranes in the apical parts of acinar cells. Images of exocytosis of zymogen granules were only few. Later, marked vacuolization and signs of autophagocytosis are seen in the basal cytoplasm. Immunohistochemistry showed that the large zymogen containing structures were intensively labelled for trypsin at the early stages of the experiment (4-30 min). Later (1-2 h), the vacuoles were empty or contained occasional, small-labelled granules only. The pancreozymin-receptor antagonist proglumide as well as cycloleucine that inhibits protein synthesis by inhibiting the synthesis of S-adenosylmethionine, effectively prevented the caerulein induced acinar cell changes. The irregular zymogen containing structures with coated pits on their surface indicate disturbed zymogen granule formation leading to the accumulation of large lakes of zymogen material and finally to marked autophagocytosis in acinar cells. The effects of caerulein are receptor-mediated and depend on the process of methylation in the formation of zymogen granules.

Acute Disease↗
PubMed2003

Involvement of local cholecystokinin in the tolerance induced by morphine microinjections into the periaqueductal gray of rats.

The ventrolateral periaqueductal gray (PAG) is a key structure for the development of opioid tolerance. An increased activity of 'anti-opioids' like cholecystokinin (CCK) has been proposed as a possible mechanism for opioid tolerance. The present study evaluates the role of PAG-located CCK in the opioid tolerance induced by repeated microinjections of morphine (MOR) into PAG. Male rats were implanted with chronic guide cannulae aimed at the PAG. Microinjection of MOR (0.5 microg in 0.5 microl) into PAG caused antinociception as quantified with the tail flick and the hot plate tests. When MOR microinjection was repeated twice daily, the antinociceptive effect disappeared within 2 days (tolerance). However, if each MOR microinjection was preceded (within 15 min) by a microinjection of the non-selective CCK receptor antagonist proglumide (PRO), (0.4 microg in 0.5 microl) into the same PAG site, the microinjections of MOR always produced antinociception and did not induce tolerance. If PRO microinjections were suspended, subsequent MOR microinjections induced tolerance. In MOR-tolerant rats, a single PRO microinjection into the same PAG site was enough to restore the antinociceptive effect of MOR. On the other hand, if CCK (1 ng in 0.5 microl) was microinjected into PAG, then MOR microinjection administered 15 min later into the same PAG site did not elicit antinociception. These results show that CCK has anti-opioid activity in PAG and that tolerance to MOR in PAG can be prevented or reversed if CCK receptors are blocked with PRO. Finally, opioid tolerance induced by repeated systemic MOR injections (5mg/kg intraperitoneal ) was reversed by a single microinjection of PRO into PAG. This emphasizes the central importance of PAG in the MOR/CCK interactions that lead to opioid tolerance.

Analgesics, Opioid↗
PubMed2001

Synthesis, molecular modeling and QSAR studies in chiral 2,3-disubstituted-1,2,3,4-tetrahydro-9H-pyrido(3,4-b)indoles as potential modulators of opioid antinociception.

In view of coexistence of opioid and cholecystokinin (CCK) in the brain areas concerned with pain processing, some semirigid racemic and chiral analogues of a potent CCK receptor antagonist (benzotript) have been synthesized and tested for their modulatory role on opioid antinociception, which may be mediated by CCK-B receptor. Some of these compounds, 3e, 3g, 3h, 4a, 4b and 4h, exhibited antinociceptive potentiation comparable to benzotript and proglumide. In order to identify the essential chemical structural features important for this potentiation, molecular modeling and quantitative structure activity relationship (QSAR) studies have been carried out in the S and R enantiomers of some of these semi-rigid compounds. The 3D-biophore models, common to all molecules of the training set have been derived. These models with superimposition (match value >0.25) depicted three biophoric sites one each for, pi/hydrophobic interactions, hydrogen bonding and ionic interactions among the phenyl/pyrrole ring, indole nitrogen, amidic oxygen, pyridyl nitrogen and lone pair of amidic oxygen. The total hydrophobicity and S absolute stereochemistry are found to positively contribute to potentiation of antinociception induced by morphine and the resulting quantitative pharmacophoric model with good correlation is found to well describe the observed activity.

Analgesics, Non-Narcotic↗
PubMed1985

Altered responding to cholecystokinins and dopaminergic agonists following 6-hydroxydopamine treatment in rats.

Production of lesions in the brain dopamine (DA) system by intraventricular injection of 6-hydroxydopamine (6-OHDA) resulted in increased responses to apomorphine (0.5 mg/kg, sc) and reduced responses to methamphetamine (0.15 mg/kg, sc). It also made animals increase responding to cholecystokinin octapeptide (CCK-8; 0.5-2 micrograms, intracerebroventricularly [icv]) and reduce responding to cholecystokinin tetrapeptide (CCK-4; 0.5-2 micrograms, icv). Response changes were quantified by measuring the level of general activity. The result indicates that DA dysfunction can affect not only DA receptor sensitivity but also the sensitivity of the CCK system. The response to CCK-8 was partially blocked by a selective CCK-8 antagonist, proglumide (5 micrograms, icv), a result suggesting the involvement of the CCK-8 receptor system. Thus, manipulation of one neuronal system could induce sensitivity changes in another closely related system.

Animals↗
PubMed1998

Inhibition of gastric emptying and intestinal transit by amphetamine through a mechanism involving an increased secretion of CCK in male rats.

1. The effect of amphetamine on gastrointestinal (GI) transit and the plasma levels of cholecystokinin (CCK) were studied in male rats. 2. Gastric emptying was inhibited both acutely and chronically by the administration of amphetamine. GI transit was decreased by the acute administration of amphetamine but not affected by the chronic administration of amphetamine. 3. Plasma CCK levels were increased dose-dependently by amphetamine. 4. Proglumide, a CCK receptor antagonist, prevented amphetamine-induced inhibition of gastric emptying and the decrease in GI transit in male rats. 5. The selective CCK(A) receptor antagonist, lorglumide, dose-dependently attenuated the amphetamine-induced inhibition of gastric emptying in male rats. In contrast, the selective CCK(B) receptor antagonist, PD 135,158, did not reverse the effect of amphetamine on gastric emptying. 6. Both lorglumide and PD 135,158 reversed the inhibitory effect of amphetamine on GI transit in male rats. 7. These results suggest that amphetamine-induced inhibition of gastric emptying and intestinal transit is due in part to a mechanism associated with the hypersecretion of endogenous CCK.

Amphetamines↗
PubMed1986

Endogenous CCK release and pancreatic growth in rats after feeding a proteinase inhibitor (camostate).

The serine proteinase inhibitor camostate was fed to rats in single, daily doses of 100 mg/kg, 200 mg/kg, and 400 mg/kg for 5, 10, or 15 days. Within 5 days, pancreatic size and protein, DNA, and enzyme content increased significantly. After prolonged administration, this trophic effect was more pronounced, and anticoordinate regulation of the synthetic rate of individual secretory proteins was observed. While enzyme content and protein synthesis of trypsinogen and chymotrypsinogen were increased, respective values for amylase were drastically reduced. Plasma levels of cholecystokinin (CCK) did not differ from controls when measured 24 h after administration of camostate. Immediately after oral feeding of camostate, CCK levels increased 10-fold above controls, reached a maximum after 90 min, and remained elevated for more than 6 h. Proglumide, a CCK-receptor antagonist, only slightly reduced the trophic action of the proteinase inhibitor. The data indicate that endogenous CCK release by a proteinase inhibitor is as potent in the modulation of pancreatic growth and individual enzyme synthesis as exogenous hormone application.

Animals↗
PubMed1990

The effect of CR 1409, a potent CCK receptor antagonist, on basal and stimulated pancreatic secretion in rat.

The effect of a specific cholecystokinin (CCK) receptor blocker from Rotta Research Laboratorium (Monza/Milano, Italy), CR 1409 (Lorglumide), on pancreatic secretion was investigated. CR 1409 caused a rightward and parallel shift in the dose-response curve of CCK-8-stimulated pancreatic protein secretion in anesthetized rats, demonstrating a competitive mechanism of inhibition. The mean pA2 value, showing the 50% inhibitory dose of CR 1409, was 6.4. CR 1409 proved to be about 1,000 times more potent as a CCK receptor blocker than proglumide, the first glutaramic acid analogue with anti-CCK potential. In conscious rats, pancreatic protein and water secretion were significantly diminished for about 2 h in response to 300 micrograms/kg of CR 1409 given subcutaneously during diversion of pancreatic juice, demonstrating inhibition of endogenous CCK by this new glutaramic acid derivative. By contrast, during reintroduction of precollected pancreatic juice into the duodenum, when the release of CCK is almost totally eliminated, pancreatic secretion was not modified by the same dose.

Animals↗
PubMed2005

Effect of cholecystokinin octapeptide on diacylglycerol-PKC signaling pathway in rat pulmonary interstitial macrophages stimulated by lipopolysaccharide.

AIM: To investigate the effect of cholecystokinin octapeptide (CCK-8) on the diacylglycerol-protein kinase C (DAG-PKC) signaling pathway in rat pulmonary interstitial macrophages (PIM) stimulated by lipopolysaccaride (LPS). METHODS: The PIM from rat lung tissues were isolated using the collagenase digestion method combined with alveolar lavage and pulmonary vessel perfusion. DAG content and PKC activity were measured by radioenzymatic assay. The translocation of PKCzeta was determined by semi-quantitative immunoblot analysis. RESULTS: CCK-8, at high concentrations (1 x 10(-6) - 1 x 10(-5) mol/L), decreased DAG content and inhibited PKC activity and PKCzeta translocation compared with that in rat resting PIM of a control group (P< 0.01). LPS increased DAG content, and promoted PKC activity and PKCzeta translocation (P< 0.01). CCK-8 decreased LPS-induced DAG content and inhibited LPS-induced PKC activity and PKCzeta translocation significantly at 1 x 10(-8) - 1 x 10(-5) mol/L (P< 0.01). This inhibitory effect of CCK-8 could be abrogated partly by proglumide (non-selective CCK receptor antagonist), CR-1409 (selective CCK-A receptor antagonist), and CR-2945 (selective CCK-B receptor antagonist) in a concentration-dependent manner (P< 0.01). CONCLUSION: CCK-8 was a negative modulator of the DAG-PKC signaling pathway in rat resting PIM, which is very important for maintaining body homeostasis. It significantly inhibited LPS-induced DAG content, PKC activity and PKCzeta translocation in a concentration-dependent manner. The CCK receptor, especially the CCK-A receptor, might play a major role in this process.

Animals↗
PubMed1982

Control of the antral motor response to feeding by gastric acid secretion in rats.

1. The motor response of the antrum to feeding was examined in relation to gastric acid content in six adult rats fitted with electrodes and strain gauges on the antrum, two of them also having a small cannula in the fundus. 2. After fasting overnight, feeding was accompanied by an immediate increase in antral activity of seventeen to nineteen strong contractions lasting 5.33 +/- 1.15 min. Both the duration and amplitude of this antral motor response were increased 2 hr after ingestion of cimetidine (20 mg/kg) or 60 min after intramuscular administration of the same dose of proglumide. 3. By contrast, the response to feeding was reduced by 43% in duration and by 58% in amplitude during an intravenous infusion of pentagastrin (5 mg/kg per hr) and disappeared after an infusion of HCl into the stomach. The area under the curve of the pressure developed by the gauge, used as a motility index, was nearly doubled when the pH of the gastric contents increased from 3.1 to 5.7 and was halved when the pH decreased from 3.1 to 2.2. 4. In normal or inhibitory gastric acid secretion, the blockade of the antral motor response to feeding appeared when the total acid content of the gastric juice reached 35-70 mu equiv/ml. 5. The results indicated that the rate of gastric secretion is of paramount importance in regulating the magnitude of the antral motor response to feeding. It is suggested that the vagally stimulated antral motility is rapidly counteracted by the increased acid secretion.

Action Potentials↗
PubMed1987

Pancreatic growth: interaction of exogenous cholecystokinin, a protease inhibitor, and a cholecystokinin receptor antagonist in mice.

The effects on pancreatic growth and plasma CCK concentration of chronic feeding of camostate (400 mg/kg day for 10 days), a potent inhibitor of serine proteases including trypsin, were assessed in the mouse. For comparison, the trophic effects of chronic exogenous administration of CCK octapeptide (sc injection of 1 microgram/kg day every eight hours for 10 days) were also studied. In addition, the effects of a proglumide-analogue CCK-receptor antagonist (CR1409) on the stimulatory actions of camostate feeding and chronic administration of exogenous CCK were studied. The effects of the combination of chronic camostate feeding and sc injections of CCK, the effects of acute camostate feeding, and the effects of the CCK-receptor antagonist given without camostate or CCK were also studied. The results show that chronic camostate feeding markedly increased CCK plasma concentrations eight-fold over control values, and that acute camostate feeding increased plasma concentration to four fold of control values. Correspondingly, chronic camostate feeding markedly increased pancreatic weight, protein and DNA content. Exogenous CCK-8 also had qualitatively similar, but quantitatively less potent stimulatory effects. The combination of camostate and CCK-8 resulted in an additive stimulatory effect. The trophic actions of exogenous and endogenous CCK grossly increased chymotrypsinogen content, but left amylase content unaffected. The CCK-receptor antagonist CR 1409 completely abolished the trophic effects of exogenous CCK and greatly inhibited the effects of chronic camostate feeding. The CCK antagonist decreased pancreatic weight, DNA and protein content compared to control values when given without any CCK or camostate. We conclude that the protease inhibitor camostate is a very strong release effector of CCK and exerts a powerful trophic effect on mouse pancreas which is probably mediated by CCK. Furthermore, physiological increases of CCK during feeding of regular chow appear to exert trophic effects on the exocrine pancreas.

Amylases↗
PubMed1987

gamma-Aminobutyric acid stimulates acid secretion from the isolated guinea pig stomach.

gamma-Aminobutyric acid (GABA) content was measured, and the effect of GABA on acid secretion was studied using the everted preparation of isolated guinea pig stomachs. GABA contents in the mucosa layer and the remaining layer were 20-24 nmol/g tissue and 34-42 nmol/g tissue, respectively. GABA at 10(-6) to 3 X 10(-5) M induced acid secretion, and the maximum secretion was obtained at 3 X 10(-5) M, that is approximately 1.6-fold of the spontaneous secretion and approximately half of the amount secreted by histamine at 3 X 10(-4) M. The GABA-induced acid secretion was inhibited by bicuculline, scopolamine, pirenzepine, proglumide, and tetrodotoxin, but not by cimetidine. Muscimol (3 X 10 to 10(-5) M), but not baclofen, induced acid secretion in a concentration-dependent manner. The responses to GABA and muscimol were antagonized by bicuculline. Scopolamine and tetrodotoxin completely inhibited the acid secretion induced by low concentrations of GABA and muscimol and to some extent the response induced by high concentrations of muscimol. All these results indicate that GABA induces acid secretion via the A type of GABA receptor, probably located mainly on the cholinergic neurons and partially on the nonneuronal cells in the guinea pig stomach.

Animals↗
PubMed1988

Cholecystokinin receptors on gallbladder muscle and pancreatic acinar cells: a comparative study.

To compare receptors for cholecystokinin (CCK) in pancreas and gallbladder, we measured binding of 125I-Bolton-Hunter-labeled CCK-8 (125I-BH-CCK-8) to tissue sections from guinea pig gallbladder and pancreas under identical conditions. In both tissues, binding had similar time-, temperature-, and pH dependence, was reversible, saturable and inhibited only by CCK related peptides or CCK receptor antagonists. Autoradiography localized 125I-BH-CCK-8 binding to the smooth muscle layer in the gallbladder. Binding of 125I-BH-CCK-8 to gallbladder sections was inhibited by various agonists with the following potencies (IC50):CCK-8 (0.4 nM) greater than des(SO3)CCK-8 (0.07 microM) greater than gastrin-17-I (1.7 +/- 0.3 microM) and by various receptor antagonists with the following potencies: L364,718 (1.5 nM) greater than CR 1409 (0.19 microM) greater than asperlicin = CBZ-CCK-(27-32)-NH2 (1 microM) greater than Bt2cGMP (120 microM). Similar potencies were found for the agonists and antagonists for pancreas sections. Inhibition of binding of 125I-BH-CCK-8 by 11 different analogues of proglumide gave similar potencies for both pancreas and gallbladder. The potencies of agonists in stimulating and antagonists in inhibiting CCK-stimulated contraction or amylase release correlated closely with their abilities to inhibit 125I-BH-CCK-8 binding to gallbladder or pancreas sections or acini, respectively. The present results demonstrate and characterize a method that can be used to compare the CCK receptors in guinea pig gallbladder and pancreas under identical conditions. Moreover, this study demonstrates that gallbladder and pancreatic CCK receptors have similar affinities for the various agonists and antagonists tested and, therefore, provides no evidence that they represent different subtypes of CCK receptors that can be distinguished pharmacologically.

Animals↗
PubMed1989

Comparative effects of CCK receptor antagonists on rat pancreatic secretion in vivo.

The present experiments evaluate in vivo effects of recently described cholecystokinin (CCK) receptor antagonists on rat pancreatic secretion. Pancreaticobiliary secretion was studied after bile duct cannulation in anesthetized rats. After two basal 10-min fractions were selected, secretion was stimulated by intravenous caerulein (0.1-30.0 micrograms/kg) or secretin, and collected for seven further 10-min fractions. Peptide antagonists (CR 1409, CR 1392, and CR 1505) and nonpeptide antagonists (asperlicin and L364,718) were given intravenously 10 min before agonists. Increasing doses of antagonists gradually reduced secretion of protein and enzymes stimulated by submaximal and maximal doses of caerulein. The antagonists did not alter nonstimulated or secretin-stimulated secretion, indicating their specificity for the CCK receptor. Except for proglumide and asperlicin, all antagonists were able to abolish caerulein-stimulated pancreatic secretion, as evaluated by the mean integrated 1-h response to a near-maximal dose of caerulein. The caerulein dose-response curve was gradually shifted to the right by increasing doses of CR 1409, indicating competitive-like kinetics. Inhibition of secretion due to supramaximal doses of caerulein, however, could be reversed by doses of CR 1409 smaller than expected from extrapolating truely competitive kinetics from an in vitro situation to the in vivo situation. The rank order of potency of the compounds to antagonize caerulein-stimulated secretion in vivo agreed with their relative potencies to antagonize caerulein-stimulated amylase secretion from pancreatic acini in vitro as well as with their affinity to bind to peripheral CCK receptors in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

Amylases↗
PubMed1987

Intracerebroventricular injection of cholecystokinin octapeptide elevates plasma prolactin levels through stimulation of vasoactive intestinal polypeptide.

We investigated the effect of cholecystokinin octapeptide (CCK-8) on plasma PRL levels in freely moving male rats. Intravenous injection of CCK-8 did not affect basal plasma PRL levels in doses up to 5000 ng/rat; however, plasma PRL increased significantly after intracerebroventricular (icv) injection of the peptide at a dose of 40 ng/rat. Proglumide (0.2 mg/kg, iv) and benzotript (0.2 mg/kg, iv), specific CCK receptor antagonists, blocked the icv CCK-8-induced increase in plasma PRL levels. There was no apparent effect of icv CCK-8 on the enhancement of PRL release by haloperidol (0.2 mg/kg, iv), sulpiride (0.1 mg/kg, iv), domperidone (0.1 mg/kg, iv), or RO22-1319 (0.1 mg/kg, iv). However, the apomorphine-induced inhibition of PRL secretion was significantly antagonized by icv CCK-8. Furthermore, icv CCK-8 increased plasma PRL levels in rats depleted of dopamine by pretreatment with reserpine and alpha-methyl-p-tyrosine. Finally, the elevation in plasma PRL levels produced by icv CCK-8 was substantially antagonized by vasoactive intestinal polypeptide antiserum (1:3; 10 microliter/rat, icv). These results suggest that CCK-8 increases plasma PRL through an interaction with a central CCK receptor, which stimulates the activity of vasoactive intestinal polypeptide, a putative PRL-releasing factor.

Animals↗
PubMed1994

Partial purification, tissue distribution and modulatory activity of a crustacean cholecystokinin-like peptide.

Reversed-phase chromatography was used to separate several forms of cholecystokinin-like peptides (CCKLP) from the pericardial organs (PCOs) of the spiny lobster Panulirus interruptus. Fast protein liquid chromatography of PCOs, stomatogastric ganglia (STGs) and eyestalks revealed five peaks of CCKLP (peaks A-E) that were common to all three tissues, as well as two additional peaks (peaks F and G) in the STG. Peaks A-E were present in the hemolymph of fed, but not starved, lobsters. The bioactivity of peaks A-E was tested on the gastric mill rhythm of the isolated STG. Only peak E elicited activity. The effects of peak E included activating the gastric mill rhythm in quiescent preparations and strengthening existing rhythms in a dose-dependent manner. Further purification of peak E by high performance liquid chromatography resolved this peak into two immunoreactive peaks, one of which retained its bioactivity. The effects of peak E were blocked by the CCK antagonist proglumide. These results are consistent with a role for peak E in the feeding-induced activation of the gastric mill.

Animals↗
PubMed1986

Reversal of antinociceptive effect of caerulein by benzodiazepine.

Benzodiazepines, chlordiazepoxide and diazepam reversed the antinociceptive action of caerulein in mice. Benzodiazepines (1-5 mg/kg) were administered intraperitoneally and 100 ng of caerulein was injected intracisternally to mice. Benzodiazepines did not change the basal pain threshold of mice but significantly antagonized the antinociceptive effect of caerulein. Proglumide (200 mg/kg, i.p.), which has been claimed to be a specific cholecystokinin receptor antagonist, could also antagonize the antinociceptive effects of caerulein. Naloxone (5 mg/kg) partially but significantly antagonized the antinociceptive effect of caerulein, suggesting that one of the mechanisms of antinociceptive action of caerulein is related to endogenous opioid peptides since benzodiazepines do not act on opioid receptors. Benzodiazepines may decrease the antinociceptive effect of caerulein through acting on cholecystokinin receptors in the central nervous system.

Analgesics↗