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PubMed1992

Autocrine stimulation of growth of AR4-2J rat pancreatic tumour cells by gastrin.

The control of cell proliferation by gastrin has been investigated in a rat pancreatic tumour cell line, AR4-2J. Exogenous gastrin, 10(-12) to 10(-8) M, stimulated cell growth of thymidine-synchronised AR4-2J cells cultured over 48 h in serum-free medium. Cell lysates of AR4-2J cells contained an average of 4.5 and 3.5 pg gastrin per 10(6) cells, when grown in serum-supplemented or serum-free media, respectively, as revealed by radioimmunoassay. In serum-free medium, AR4-2J secrete 34 ng 1(-1) 10(-6) cells of gastrin over 48 h. Addition of an anti-gastrin immunoglobulin preparation, but not control immunoglobulins, caused a maximum 52% reduction in cell growth. These data are consistent with an autocrine role for gastrin in the control of AR4-2J cell growth. These results were supported by studies with gastrin/CCK receptor antagonists. Six non-peptide gastrin/CCK receptor antagonists inhibited AR4-2J cell growth in a concentration-related manner. The concentration required for 50% inhibition (IC50) of cell growth by the amino acid-derived antagonists proglumide (3.5 x 10(-3) M), benzotript (1.8 x 10(-3) M), loxiglumide (1.1 x 10(-4) M) and lorglumide (6.7 x 10(-5) M) were of the same order and significantly correlated with their IC50 for inhibition of 125I-gastrin binding to AR4-2J cells. Inhibition of cell growth by these antagonists was partially reversed by the addition of exogenous gastrin. In contrast, the IC50 for inhibition of cell growth with two benzodiazepine-derived antagonists, the CCK-B receptor antagonist L-365,260 (4.6 x 10(-5) M) and the CCK-A receptor antagonist devazepide (1.7 x 10(-5) M) were two-three orders of magnitude greater than those required to inhibit gastrin binding (10(-8)-10(-7) M). The growth inhibitory effects of L-365,260 and devazepide were not reversed by exogenous gastrin suggesting these benzodiazepine-derived antagonists do not inhibit cell growth by interaction with gastrin receptors. The results are consistent with gastrin being an autocrine growth factor in AR4-2J cells, and that stimulation of cell growth is due to stimulation of the gastrin, rather than CCK-B, receptor sub-type. This study highlights that gastrin receptor antagonists warrant further investigation as agents to control growth of tumours, such as those from the gastrointestinal tract, which express gastrin receptors.

Animals↗
PubMed1999

Pharmacological analysis of CCK2 receptor antagonists using isolated rat stomach ECL cells.

1. Gastrin stimulates rat stomach ECL cells to secrete histamine and pacreastatin, a chromogranin A (CGA)-derived peptide. The present report describes the effect of nine cholecystokinin2 (CCK2) receptor antagonists and one CCK1 receptor antagonist on the gastrin-evoked secretion of pancreastatin from isolated ECL cells. 2. The CCK2 receptor antagonists comprised three benzodiazepine derivatives L-740,093, YM022 and YF476, one ureidoacetamide compound RP73870, one benzimidazole compound JB 93182, one ureidoindoline compound AG041R and three tryptophan dipeptoids PD 134308 (CI988), PD135158 and PD 136450. The CCK1 receptor antagonist was devazepide. 3. A preparation of well-functioning ECL cells (approximately 80% purity) was prepared from rat oxyntic mucosa using counter-flow elutriation. The cells were cultured for 48 h in the presence of 0.1 nM gastrin; they were then washed and incubated with antagonist alone or with various concentrations of antagonist plus 10 nM gastrin (a maximally effective concentration) for 30 min. Gastrin dose-response curves were constructed in the absence or presence of increasing concentrations of antagonist. The amount of pancreastatin secreted was determined by radioimmunoassay. 4. The gastrin-evoked secretion of pancreastatin was inhibited in a dose-dependent manner. YM022, AG041R and YF476 had IC50 values of 0.5, 2.2 and 2.7 nM respectively. L-740,093, JB93182 and RP73870 had IC50 values of 7.8, 9.3 and 9.8 nM, while PD135158, PD136450 and PD134308 had IC50 values of 76, 135 and 145 nM. The CCK1 receptor antagonist devazepide was a poor CCK2 receptor antagonist with an IC50 of about 800 nM. 5. YM022, YF476 and AG041R were chosen for further analysis. YM022 and YF476 shifted the gastrin dose-response curve to the right in a manner suggesting competitive antagonism, while the effects of AG041R could not be explained by simple competitive antagonism. pK(B) values were 11.3 for YM022, 10.8 for YF476 and the apparent pK(B) for AG041R was 10.4.

Animals↗
PubMed1995

The role of the Val353 residue in antagonist binding to rat CCK-B receptors.

The Val353 residue of the rat cholecystokinin-B (CCK-B) receptor was mutated to Leu to test whether this residue is part of a binding site for antagonists having different chemical structures. The agonist radioligand [3H]SNF 8702 showed similar affinity for both wild-type and mutant receptors. Mutation of the CCK-B receptor reversed the order of affinities for the asperlicin derivatives from L-365,260 > devazepide (wild-type) to devazepide > L-365,260 (mutant) but had no effect on the affinity of the peptoid CCK-B receptor antagonist Cam-1028. The results show that Val353 is not part of a general CCK-B receptor antagonist recognition site and that Cam-1028 is recognized at a receptor site distinct from that binding asperlicin derivatives.

Amino Acids↗
PubMed1992

Functional comparisons of gastrin/cholecystokinin receptors in isolated preparations of gastric mucosa and ileum.

1. The gastrin cholecystokinin (CCK) receptors mediating stimulation of acid secretion in rat isolated gastric mucosa (RGM) and contraction in guinea-pig isolated ileum longitudinal muscle-myenteric plexus (GPI) have been characterized by use of peptide agonists and the non-peptide antagonists, lorglumide, devazepide and L-365,260. 2. In RGM, gastrin peptides (sulphated gastrin heptadecapeptide (G-17), non-sulphated (ns) G-17 and pentagastrin) were potent agonists of acid secretion (EC50 values of 4.3, 16 and 27 nM respectively). Sulphated CCK octapeptide (CCK-8) was also a potent agonist, (EC50 = 0.9 nM), but was less efficacious, producing a lower maximal response. In contrast, in GPI, CCK-8 was a potent full agonist (EC50 = 1.4 nM) and was more than 1000 times more potent than the gastrin peptides in producing a sustained contractile response. 3. In GPI, CCK-8 (0.1 to 100 nM) produced sustained contractile responses, whilst CCK-4 (3 to 1000 nM) produced transient responses. These responses had different sensitivities to atropine (1 microM), suggesting that more than one receptor may mediate contraction in this tissue. 4. In RGM, L-365,260 was the most potent antagonist of pentagastrin-stimulated acid secretion (pA2 = 7.6). This functional affinity estimate was similar to that for L-365,260 as an antagonist of excitatory responses in rat ventromedial hypothalamic slices (Kemp et al., 1989) but differed from binding affinity estimates in guinea-pig cortex and gastric glands (Freidinger, 1989). 5. In GPI, devazepide, L-365,260 and lorglumide yielded different affinity estimates when compared against CCK-8 and CCK-4 or pentagastrin respectively.These studies were consistent with the view that the sustained response produced by CCK-8 was mediated by CCKA receptors and the transient response produced by CCK-4 and pentagastrin was mediated by CCKB receptors.6. Affinity estimates for L-365,260 and lorglumide against CCK-4 or pentagastrin in GPI were significantly different from corresponding estimates against pentagastrin in RGM. These studies are consistent with the view that gastrin/CCKB receptors in GPI may differ from those in RGM.

Animals↗
PubMed1995

Interaction between CCK and opioids in the modulation of the rectocolonic inhibitory reflex in rats.

The effects of cholecystokinin octapeptide (CCK-8) as well as the involvement of opioid system were evaluated in rectal distension (RD)-induced colonic motor inhibition in rats. Rats were surgically prepared with electrodes implanted on the proximal colon, and a catheter was implanted in lateral ventricle of the brain. RD was performed by inflation (0.0-1.6 ml) of a balloon rectally inserted. RD 1.6 ml of induced an inhibition of the colonic spike bursts (3.1 +/- 0.5 per 5 min vs. 8.1 +/- 0.4 before RD). Intracerebroventricular but not intravenous injection of CCK-8 and A-71623 (50 and 100 ng/kg) reduced the RD-induced colonic motor inhibition, whereas A-63387 was ineffective. PD-135,158 (10 micrograms/kg icv) suppressed the inhibitory reflex caused by RD. Devazepide (100 micrograms/kg icv) had no effect in this reflex function. Devazepide (1 microgram/kg), naloxone (0.1 mg/kg), and nor-binaltorphimine (nor-BNI; 10 mg/kg) reversed the blocking effect of CCK-8, whereas PD-135,158 (0.1 microgram/kg) and naltrindole (1 mg/kg) have no effect. In conclusion, CCK-8 acts on central alimentary cholecystokinin receptors to modulate the RD-induced inhibition of colonic motility through pathways involving activation of endogenous kappa-receptors.

Animals↗
PubMed1996

Peripheral bombesin induces gastric vagal afferent activation in rats.

Bombesin's influence on gastric vagal afferent discharge (GVAD) was studied in urethan-anesthetized rats. Vehicle and peptides were injected intravenously at 30-min intervals. Cholecystokinin (CCK; 300 pmol) and bombesin (300 pmol) increased ongoing multiunit GVAD by 153 +/- 59 and 162 +/- 37%, respectively; similar increases were induced by a second injection of bombesin and CCK. The bombesin antagonist, ICI-216140, prevented bombesin-induced increase in GVAD, whereas the CCK response was not influenced. The CCK-A receptor antagonist devazepide reduced the activation of GVAD induced by bombesin from 107 +/- 11 to 63 +/- 6%, while abolishing the CCK response. Devazepide given alone or in combination with ICI-216140 did not modify gastric distension (3 ml)-induced increase in GVAD. Of 22 single units that were activated by gastric load (4 ml), 17 and 20 units responded also to bombesin (620 pmol) and CCK (870 pmol), respectively. Of the nine units that did not respond to gastric load, eight had an increase in GVAD induced by both bombesin and CCK. There was no specific binding of 125I-labeled [Tyr4]bombesin on cervical vagus, either intact or 24 h after ligation. These data suggest that intravenous bombesin-induced stimulation of GVAD is indirect and initially mediated through specific receptor activation influencing gastric smooth muscle and the release of CCK.

Animals↗
PubMed2001

Deficits in E2-dependent control of feeding, weight gain, and cholecystokinin satiation in ER-alpha null mice.

To test the role of gene expression of the classical ER (ER alpha) in the inhibitory effects of E on food intake and body weight, we ovariectomized and administered E2 benzoate (75 pg/d) or vehicle to wild-type (WT) mice and mice with a null mutation of ER alpha (alpha ERKO). Mice were ovariectomized at age 9 wk, at which time there was no significant effect of genotype on food intake or body weight. During an 18-d test after recovery from ovariectomy, vehicle-treated WT mice increased daily food intake and gained more body weight than E2-treated WT mice, whereas food intake and body weight gain were not different in E2- and vehicle-treated alpha ERKO mice. Carcass analysis revealed parallel changes in body lipid content, but not water or protein content. Because an increase in the potency of the peripheral cholecystokinin (CCK) satiation-signaling system mediates part of E2's influence on feeding in rats, the influence of ip injections of 250 microg of the selective CCK(A) receptor antagonist devazepide was then tested. Devazepide increased 3-h food intake in E2-treated WT mice, but was ineffective in both groups of alpha ERKO mice. Furthermore, ip injections of 4 microg/kg CCK-8 increased the number of cells expressing c-Fos immunoreactivity in the nuclei of the solitary tract of E2-treated WT mice more than it did in vehicle-treated WT mice, whereas E2 had no such effect in alpha ERKO mice. Thus, ER alpha is necessary for normal responsivity of food intake, body weight, adiposity, and the peripheral CCK satiation-signaling system to E2 in mice, and ER beta is not sufficient for any of these effects. This is the first demonstration that ER alpha gene expression is involved in the estrogenic control of feeding behavior and weight regulation of female mice.

Animals↗
PubMed2000

Acute taurodeoxycholate-induced pancreatitis in the rat is associated with hyperCCKemia.

BACKGROUND: Cholecystokinin (CCK) has been suggested to be involved in the development and course of acute pancreatitis. In the present study we measured plasma CCK concentrations in acute experimental pancreatitis (AEP) in the rat, and evaluated the role of circulating CCK levels on the initial pancreatic damage in pancreatitis. METHODS: Endogenous hyperCCKemia was induced by surgical biliodigestive shunt (BDS) and exogenous hyperCCKemia by infusion of CCK-8S. The CCK-A receptor antagonist devazepide was used to antagonize the effect of CCK. Pancreatitis was induced by pancreatic duct infusion of sodium taurodeoxycholate 4 wk after the BDS operation or 1 wk after the start of the infusions. Nonpancreatitic sham- and BDS-operated rats, respectively, were used as control animals as were groups of otherwise untreated rats with pancreatitis. The animals were sacrificed 6 h after induction of pancreatitis. Concentrations of CCK were determined in plasma as were protein and amylase levels in the pancreas and peritoneal exudates. The extent of pancreatic necroses was assessed microscopically. RESULTS: Pancreatitis caused an 11-20-fold increase of circulating CCK as measured after 6 h. In pancreatitic rats with induced hyperCCKemia, there was a further marked increase of plasma CCK. Pancreatic weight and edema, protein and amylase contents, and extent of necroses were the same regardless of the level of plasma CCK. Devazepide had no influence on the studied pancreatic parameters. CONCLUSION: We conclude that acute taurodeoxycholate-induced pancreatitis in the rat is associated with elevated plasma CCK concentrations. There seems, however, not to be any correlation between the degree of hyperCCKemia and the extent of initial pancreatic damage.

Acute Disease↗
PubMed2005

Effects of cholecystokinin-receptor antagonists on Fos-like immunoreactivity stimulated by sulfated cholecystokinin-8 in neurons of the myenteric plexus and hindbrain of rats.

OBJECTIVE: To evaluate the role of cholecystokinin (CCK)-receptor antagonists in the activation of enteric and hindbrain neurons by sulfated CCK-8. ANIMALS: 81 male Sprague-Dawley rats. PROCEDURE: Rats were allocated to 10 groups (5 to 22 rats/group). Each rat received 2 IP injections (15 minutes between injections). The first injection consisted of a specific CCK2-receptor (CCK2R) antagonist (L365,260; 150, 500, or 1,000 microg/kg), a specific CCK1-receptor (CCK1R) antagonist (devazepide; 150 microg/kg), or 1% dimethyl sulfoxide (DMSO [ie, vehicle]), and the second injection consisted of sulfated CCK-8 (10 microg/kg) or saline (0.9% NaCl) solution. Rats were anesthetized and perfused with 500 mL of Krebs saline solution, and the myenteric plexuses of the duodenum and jejunum were collected. Rats were then perfused with 500 mL of phosphate-buffered 4% formaldehyde solution; rats were then euthanatized, and the hindbrain of each was harvested. Tissues were stained by use of a diaminobenzidine reaction enhanced with nickel to reveal Fos-like immunoreactivity (Fos-LI), a marker of neuronal activation, in the aforementioned neurons. RESULTS: Sulfated CCK-8 significantly increased Fos-LI in the myenteric and hindbrain neurons, compared with values for the DMSO injections. All dosages of L365,260 failed to attenuate this increase; however, injection of devazepide attenuated the increase in Fos-LI. CONCLUSIONS AND CLINICAL RELEVANCE: Analysis of the results of this study reveals that sulfated CCK-8 activates myenteric and hindbrain neurons of rats primarily through CCK1 R. It provides evidence that CCK2R are lacking or not functional in the gastrointestinal tract of rats.

Animals↗
PubMed1996

Opposing effects of CCK(A) and CCK(B) antagonists on the development of conditioned activity in rats.

Cholecystokinin (CCK) is co-localized with dopamine (DA) in portions of the mesolimbic system. Evidence suggests that CCK(B) receptor mechanisms mediate an inhibitory effect on DA function while CCK(A) receptor mechanisms mediate a facilitory effect on DA function. As DA has been implicated in the acquisition of conditioned activity, the present experiments investigated the interaction between selective CCK(A) and CCK(B) receptor antagonists on the development of conditioned activity. Experiment 1 determined whether the CCK(B) receptor antagonist, L-365,260 (0.01, 0.1 and 1.0mg/kg, i.p.) would induce conditioned activity. Paired groups received four two-hour drug-environment pairings whereas Unpaired groups received the two stimuli explicitly unpaired. The group that received L-365,260 (0.mg/kg) paired with the test environment subsequently showed increased activity in that environment in a drug-free test day. Experiment 2 examined the interaction of pre-treatment with the CCK(A) receptor antagonist, devazepide (0, 0.001, 0.01 and 0.1mg/kg) on the conditioned activity induced by L-365,260 (0.1mg/kg). Devazepide impaired the acquisition of L-365,260 conditioned activity. These studies suggest that CCK mechanisms play a key role in the development of conditioned activity and extend previous research suggesting a bi-directional function for CCK(A) and CCK(B) receptors.

Journal Article↗
PubMed1998

Mesenteric afferent sensitivity to cholecystokinin and 5-hydroxytryptamine.

The present electrophysiological investigation examines the effect of CCK and 5-hydroxytryptamine on gastrointestinal afferent fibre discharge. 5-HT markedly stimulated mesenteric afferents. The response was transient (< 10s) and mediated by 5-HT3 receptors as demonstrated by the action of 2-methyl-5-HT and antagonism by granisetron. CCK was also a potent stimulus to mesenteric afferents causing a long-lasting (> 30s) increase in excitability. The response to CCK was mediated via the CCKA receptor as shown by the antagonistic action of devazepide. At doses of granisetron and devazepide which completely block the response to exogenous 5-HT and CCK, the afferent fibres still responded to both mechanical and chemical stimulation of the mucosa. Thus products of enteroendocrine cells can have profound effects on mucosal afferent sensitivity but do not play an obligatory role in afferent signal transduction.

Animals↗
PubMed2001

Cholecystokinin receptor antagonists increase the rat pup's preference toward maternal-odor and rug texture.

The role of the cholecystokinin (CCK) system in mediating the infant's natural preferences toward maternal-related stimuli was examined by peripheral administration of selective CCK(A) and CCK(B) receptor antagonists (Devazepide and L-365,260, respectively) to 11-12-day-old rats and presenting them with a 3-minute preference test. In Experiment 1, the choice was between two floor textures, rug and plywood; the time spent on the relatively preferred side (rug) was measured. In Experiment 2, the odor of maternal faces emanated from one end of the test arena; time spent near that end was measured. These sensory stimuli were chosen as they represent olfactory and tactile aspects of the dam and nest. Compared to controls, both CCK receptor antagonists selectively increased the time spent on the preferred side, in both experiments, without affecting axillary temperature or locomotor activity. The results suggest that CCK may mediate and attenuate the infant's attraction toward naturally preferred stimuli.

Animals↗
PubMed2006

The ontogeny of postingestive inhibitory stimuli: examining the role of CCK.

Cholecystokinin (CCK) inhibits food intake in adults. This paper describes research examining the ability of CCK to affect feeding in infant rats and the role of CCK in the developmentally emerging ability of the rat pup to inhibit ingestion in response to sensory characteristics of food. First, data will be described from studies that asked if the CCK system is functional in preweanling rats. Specifically, these studies examined whether exogenous and endogenous CCK can decrease intake of the infant rat during independent ingestion (of a milk diet, away from the dam). In addition, the ability of exogenous CCK to activate central feeding-control areas in the brain stem and hypothalamus in infant rats was examined by C-FOS staining. Next, experiments examining which specific intake-inhibitory sensory aspects of food are mediated by CCK will be described. The volume, hypertonicity, fat, carbohydrate and protein content of a preload were separately manipulated in different studies, followed closely by a 30-min test meal. The selective CCK(1) receptor antagonist devazepide was used to assess CCK mediation of the control of intake produced by particular sensory aspects of food, at the earliest age in which this ability to control intake appears. Finally, the pattern of independent ingestion in infant OLETF rats lacking CCK(1) receptors was examined. The results suggest that the CCK intake-inhibitory mechanism is potentially available to the young, suckling pup even before it starts to feed on its own. However, it appears to mediate only a portion of the controls of intake during nursing and early stages of weaning. Some aspects of the CCK system (e.g., forebrain-hindbrain connections) and CCK's role in mediating the effects of other stimulus aspects of food apparently undergo a post-weaning maturational process.

Animals↗
PubMed1995

Role of N-methyl-D-aspartic acid and cholecystokinin receptors in apomorphine-induced aggressive behaviour in rats.

We studied the aggressive behaviour induced by repeated treatment with apomorphine, a dopamine agonist (0.5 mg/kg s.c. twice daily, 10 days), in rats. The first signs of defensive aggressiveness appeared on the third day of apomorphine treatment and were generally seen on the 7th day. Aggressiveness induced by a challenge dose of apomorphine (0.5 mg/kg s.c.) on the 11th day was antagonized by haloperidol (0.05 and 0.1 mg/kg i.p.) and clozapine (10 mg/kg i.p.). An antagonist of N-methyl-D-aspartate (NMDA)-gated channels, dizocilpine (MK-801), also blocked the aggressive behaviour at 0.25 and 0.5 mg/kg i.p. but caused ataxia. When dizocilpine (0.25 mg/kg i.p.) and apomorphine were coadministered for 10 days, aggressive behaviour did not develop. At 0.025 mg/kg i.p., dizocilpine even accelerated the appearance of apomorphine-induced aggressive behaviour, which manifested on the 3rd day in all rats. In a separate study, a 7-day treatment with dizocilpine (0.25-1 mg/kg i.p.) of rats, sensitized by a prior 10-day apomorphine treatment, did not reverse the established aggressive behaviour. The coadministration of apomorphine and cholecystokinin (CCK) -A or -B antagonists, devazepide or L-365,260 (0.01-2.5 mg/kg i.p.) respectively, neither affected development of apomorphine-induced aggressive behaviour nor intensity of aggressiveness in the sensitized rats. In binding studies neither density nor affinity of striatal dopamine D2 receptors was changed by acute or chronic apomorphine treatment. The number of [3H]pCCK-8 binding sites in the frontal cortex increased already after a single injection of apomorphine.(ABSTRACT TRUNCATED AT 250 WORDS)

Aggression↗
PubMed1996

The cholecystokinin receptor antagonist L-364,718 reduces taurocholate-induced pancreatitis in rats.

CONCLUSION: Our results suggest that the cholecystokinin (CCK) receptor antagonist L-364,718 has a protective effect on taurocholate-induced pancreatitis, and thus, it is inferred that CCK may have a significant pathophysiological role in the early phase of pancreatitis. BACKGROUND: Conflicting results have been obtained from studies designed to determine the role of CCK in the initial stages of pancreatitis. METHODS: We evaluated the protective effect of the CCK receptor antagonist L-364,718 (devazepide) and of the trypsin inhibitor camostat, on taurocholate-induced pancreatitis in rats. L-364,718 (1 mg/kg) or camostat (200 mg/kg) was administered intragastrically 30 min before the induction of pancreatitis. RESULTS: Infusion of sodium taurocholate (50 mg/kg) into the pancreaticobiliary duct caused severe pancreatitis with marked hyperamylasemia and reduction of tissue enzyme content at 12 h postinfusion. Pretreatment with L-364,718, but not with camostat, caused significant improvement in signs of experimental pancreatitis based on tissue enzyme content and morphology. Compared with untreated pancreatitis, there was relatively well-preserved lobular architecture, less edema, less infiltration of inflammatory cells, and more zymogen granules after L-364,718 pretreatment. Moreover, the reduction of enzyme content owing to pancreatitis was ameliorated by L-364,718 pretreatment.

Amylases↗
PubMed2003

Pharmacological effects of oxytocin on gastric emptying and intestinal transit of a non-nutritive liquid meal in female rats.

The effects of oxytocin (OT) on gastric emptying, gastrointestinal transit, and plasma levels of cholecystokinin (CCK) were studied in female rats. Gastrointestinal motility was assessed in rats 15 min after intragastric instillation of a test meal containing charcoal and Na(2)(51)CrO(4). Gastric emptying was determined by measuring the amount of radiolabeled chromium contained in the small intestine as a percentage of the initial amount received. Gastrointestinal transit was evaluated by calculating the geometric center of distribution of the radiolabeled marker. Blood samples were collected for CCK radioimmunoassay. After administration of OT (0.2-0.8 mg/kg), gastric emptying and gastrointestinal transit were inhibited, whereas the plasma concentration of CCK was increased in a dose-dependent manner. Atosiban, an oxytocin receptor antagonist, effectively attenuated the OT- induced inhibition of gastric emptying and gastrointestinal transit. However, administration of atosiban alone had no effect on gastric emptying and gastrointestinal transit. The selective CCK(1) receptor antagonists, devazepide and lorglumide, effectively attenuated the OT-induced inhibition of gastric emptying and gastrointestinal transit. L-365, 260, a selective CCK(2) receptor antagonist, did not alter the OT-induced inhibition of gastric emptying and gastrointestinal transit. These results suggest that OT inhibits gastric emptying and gastrointestinal transit in female rats via a mechanism involving CCK stimulation and CCK(1) receptor activation.

Animals↗
PubMed2002

Involvement of cholecystokinin receptor in the inhibition of gastric emptying by oxytocin in male rats.

The effects of oxytocin (OT) on gastric emptying and plasma levels of cholecystokinin (CCK) were studied in male rats. Gastrointestinal motility was assessed in rats 15 min after intragastric instillation of a test meal containing charcoal and Na2(51)CrO4. Gastric emptying was determined by measuring the amount of radiolabeled chromium contained in the small intestine as a percentage of the initial amount received. Blood samples were collected for OT and CCK radioimmunoassay. After administration of OT (0.2-0.8 mg x kg(-1)), gastric emptying was inhibited, whereas plasma concentrations of OT and CCK were increased in a dose-dependent manner. Atosiban, an oxytocin receptor antagonist, effectively attenuated the OT-induced inhibition of gastric emptying. However, administration of atosiban alone had no effect on gastric emptying. Devazepide (3 mg x kg(-1)), a selective CCKA receptor antagonist, effectively attenuated the OT-induced inhibition of gastric emptying. L-365, 260, a selective CCKB receptor antagonist, did not alter the OT-induced inhibition of gastric emptying. These results suggest that OT inhibits gastric emptying in male rats via a mechanism involving CCK stimulation and CCKA receptor activation.

Animals↗
PubMed1996

Participation of central descending nociceptive facilitatory systems in secondary hyperalgesia produced by mustard oil.

The present series of experiments were designed to examine a potential role for central descending pain facilitatory systems in mediating secondary hyperalgesia produced by topical application of mustard oil and measuring the nociceptive tail-flick reflex in awake rats. Topical application of mustard oil (100%) to the lateral surface of the hind leg produced a facilitation of the tail-flick reflex that was significantly reduced in spinal transected animals. Mustard oil hyperalgesia was also inhibited in animals that had received electrolytic lesions in the rostral ventromedial medulla (RVM). Intrathecal (i.t.) administration of the non-selective cholecystokinin (CCK) receptor antagonist proglumide (10 micrograms) prior to mustard oil application completely blocked both the lesser and greater hyperalgesic responses observed in spinal transected and normal animals, respectively, and produced an inhibition of the tail-flick reflex in normal animals. Administration of the selective CCKB receptor antagonist L-365260 i.t. dose-dependently inhibited mustard oil hyperalgesia (ID50 = 364 ng) at doses approximately 5-fold less than the CCKA receptor antagonist devazepide (ID50 = 1760 ng). Similar to spinal proglumide, microinjection of the neurotensin antagonist SR48692 (3.5 micrograms) into the RVM blocked mustard oil hyperalgesia and inhibited the tail-flick reflex. These data suggest that secondary hyperalgesia produced by mustard oil is mediated largely by a central, centrifugal descending pain facilitatory system which involves neurotensin in the RVM and spinal CCK (via CCKB receptors). The inhibition of the tail-flick reflex produced by mustard oil following spinal or supraspinal administration of receptor antagonists suggests concurrent activation of central descending facilitatory and inhibitory systems.

Animals↗