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[The participation of CCK-8-ergic mechanisms in the regulation of emotional behavior in rodents].

Effects of CCK-8 receptor agonists caerulein and pentagastrin and CCK-8 receptor antagonist proglumide on exploratory and locomotor activity of mice and rats were studied. Systemic administration of caerulein (500 ng/kg 1 mcg/kg) decreased significantly the exploratory activity of mice in elevated plus-maze. This anxiogenic-like action of caerulein was attenuated by acute pretreatment with proglumide (1 and 15 mg/kg) but not with diazepam (up to 0.75 mg/kg). Proglumide slightly increased the exploratory activity of rats in plus-maze; on the other hand, caerulein and pentagastrin potently decreased the measures of exploration in this test. Caerulein (10-100 mcg/kg) and proglumide (1 and 15 mg/kg) inhibited 3H-pentagastrin binding in mice brain in in vivo experiments. The data obtained indicate that CCK-8-ergic mechanisms in brain play an important role in the generation of anxiety states in rodents.

Animals↗
PubMed1986

Antagonists of central and peripheral behavioral actions of cholecystokinin octapeptide.

Pharmacological studies on the behavioral functions of sulfated cholecystokinin (CCK) in the gut and in the brain require potent, specific antagonists to CCK. Compounds identified as competitive antagonists at the peripheral receptors for CCK were tested for their ability to block the behavioral effects of CCK administered centrally and peripherally. Behavioral effects of CCK (8.8 X 10-10 mmol) administered centrally into the nucleus accumbens, i.e., potentiation of dopamine-induced hyperlocomotion in rats, were effectively blocked by pretreatment with proglumide (6 X 10(-5) mmol of nucleus accumbens), by benzotript (3 X 10(-5) mmol of nucleus accumbens) and by rabbit antiserum raised against CCK (0.2 microliter/nucleus accumbens), but not by CCK26-33 (1.7 X 10(-7) mmol) or unsulfated CCK26-33 (1.9 X 10(-6) mmol). The behavioral effects of peripherally administered CCK, i.e. reduced food consumption and reduced exploratory behaviors in mice, were blocked effectively by pretreatment with proglumide (0.3-0.9 mmol/kg), and by benzotript (0.03 mmol/kg), but not by CCK30-33 (0.003 mmol/kg). None of the compounds administered peripherally significantly affected food consumption or exploratory behaviors when given alone. Furthermore, none of the compounds significantly affected locomotion when administered alone into the nucleus accumbens, or significantly affected dopamine-induced hyperlocomotion when given into the nucleus accumbens before dopamine. Benzotript, proglumide and a CCK antibody appear to act as specific antagonists of the behavioral effects of CCK at both the peripheral gastrointestinal site and at the central nucleus accumbens site. Neither unsulfated CCK26-33 or CCK30-33 were effective as antagonists of peripheral or central behavioral effects of CCK. However, whereas benzotript and proglumide may be useful as pharmacologically specific antagonists, the high doses required suggest that more potent CCK antagonists are required for investigating the behavioral functions of endogenous CCK.

Animals↗
PubMed1988

Fade and tachyphylaxis of gastric acid secretory response to pentagastrin in rat isolated gastric mucosa.

1. Gastric acid secretory responses to pentagastrin were characterized in the rat isolated gastric mucosa. In particular, the mechanisms underlying fade, declining response upon continued stimulation, and tachyphylaxis, progressively reduced responses upon repeated stimulation, were investigated. 2. Pentagastrin, 10(-9)-10(-7) M, resulted in concentration-related increases in acid secretion, with a mean maximum of 2.65 mumol cm-2 h-1 in response to pentagastrin, 10(-7) M. Higher concentrations of pentagastrin produced sub-maximal secretory rates; we define this as auto-inhibition. The responses to all concentrations of pentagastrin demonstrated fade. The rate of fade was correlated with the maximum acid secretory rate, declining at about 36% of the peak over the first 16 min. 3. The PO2, PCO2, [HCO3-], pH, [glucose], [lactate], [Na+] and [K+] did not decline during the fade of the acid secretory response to pentagastrin, 10(-7) M. Addition of a second aliquot of pentagastrin was not able to reverse fade, but these tissues were responsive to histamine. Replacement of the serosal solution, before addition of a second aliquot of pentagastrin, increased the acid response from 3% to 24% of the first response. 4. Serosal solution from donor tissues, allowed to respond to pentagastrin and then the acid secretion to fade, was able to stimulate secretion in fresh recipient tissues, although at lower rates. 5. Acid secretory responses to a second dose of pentagastrin were not significantly different, whether the tissues were previously unstimulated, or stimulated with pentagastrin washed out after attaining its peak secretory response (after 10-20 min). The second response was significantly reduced if the first response was allowed to fade with the pentagastrin in contact for 100 min; i.e. fade significantly influenced the extent of tachyphylaxis. 6. Proglumide, 10(-2) M, a gastrin receptor antagonist, and omeprazole, 10(-5) M, an inhibitor of the gastric (H+ + K+)-ATPase, both inhibited pentagastrin-stimulated acid secretion to similar extents. The second response to pentagastrin after pentagastrin alone, or pentagastrin plus omeprazole were both reduced compared to responses after no stimulation or omeprazole alone, respectively. After pentagastrin plus proglumide, the second response to pentagastrin was not lower than after proglumide alone. Proglumide, but not omeprazole, therefore, prevented pentagastrin tachyphylaxis. 7. It is concluded that gastrin fade and tachyphylaxis are related phenomena. Part of the fade may be due to release of an inhibitor(s). The major proportion of tachyphylaxis is a result of specific interaction of gastrin with its receptors.

Animals↗
PubMed1990

Pancreatic receptors for cholecystokinin: evidence for three receptor classes.

For inhibition of binding of 125I-Bolton-Hunter-labeled cholecystokinin octapeptide (125I-BH-CCK-8) to guinea pig pancreatic acini, the potencies for agonists were CCK-8 greater than desulfated [des(SO3)] CCK-8 greater than gastrin-17-I greater than pentagastrin greater than CCK-4 and for the antagonists L 364718 greater than proglumide analogue 10 greater than CBZ-CCK-(27-32)-NH2. For all non-sulfated agonists, the curves were biphasic with 20% of the tracer bound to sites with high affinity for these agonists with the following relative potencies: gastrin-17-I greater than pentagastrin greater than des(SO3)CCK-8 much greater than CCK-4; whereas 80% was bound to low-affinity sites with the following potencies: des(SO3)CCK-8 greater than gastrin-17-I = pentagastrin much greater than CCK-4. For L 364718 and proglumide analogue 10, 80% of 125I-BH-CCK-8 was bound to sites with high affinity for these antagonists and 20% to sites with low affinity. Analysis of the dose-inhibition curve for CCK-8 demonstrated two binding sites; however, comparison with the analysis in the presence of 0.1 microM gastrin-17-I suggested three binding sites. The gastrin-17-I dose-inhibition curve was significantly better fit by a three-site model than by a two-site model. The affinities of the various agonists and antagonists for the three sites were compared with their abilities to inhibit binding of 125I-gastrin-I and either stimulate or inhibit CCK-8-stimulated amylase release. These results demonstrate that 125I-BH-CCK-8 binds to three classes of receptors, not two as reported previously. Two classes are CCK-preferring, bind 83% of 125I-BH-CCK-8 at tracer concentrations, and comprise high- and low-affinity CCK-preferring sites that can be distinguished by all agonists but have equally high affinity for L 364718 and proglumide 10. A third class binds 17% of the tracer, cannot be differentiated from high-affinity CCK-preferring receptors by CCK-8, and has low affinities for L 364718 and proglumide 10. Future studies relating binding of 125I-BH-CCK-8 to biological activity or characterization of the CCK receptor by using radiolabeled agonists should consider CCK interaction with three receptors, not two as was done in the past.

Animals↗
PubMed1985

Cholecystokinin-dopamine receptor interactions as studied with cholecystokinin receptor antagonists.

It has previously been shown that cholecystokinin octapeptide (CCK-8) can modulate the binding of dopaminergic agonists and antagonists to brain homogenates in vitro. The present study was designed to more carefully address the possibility that CCK-8 could modulate the number of affinity of rat striatal D2 receptors. It was found that (1) unsulfated CCK-8 will antagonize the binding of tritiated spiperone to D2 receptors, but sulfated CCK-8 is considerably less potent; (2) the putative CCK antagonists benzotript, proglumide, and the phenoxyacetyl derivative of proglumide were without effect upon tritiated spiperone binding to D2 receptors up to concentrations of 100 microM; (3) the phenoxyacetyl derivative of proglumide, a potent CCK antagonist in the periphery, is only modestly more potent than proglumide in CCK receptor binding assays using 125-I-(Bolton-Hunter)-CCK-8. It is suggested that the modulatory actions of CCK upon D2 receptors do not appear to proceed through a recognition site corresponding to the conventional pharmacological definition of a neuronal CCK receptor.

Animals↗
PubMed1985

Cholecystokinin antagonists selectively potentiate analgesia induced by endogenous opiates.

We have recently observed that exogenous sulfated cholecystokinin octapeptide (CCK) can antagonize various forms of opiate analgesia and that the CCK receptor blocker proglumide potentiates morphine analgesia. These observations, plus the similarity in the distribution of CCK and opiate systems, suggest that endogenous CCK may act as a physiological opiate antagonist. We have extended these initial studies by examining the effect of CCK antagonists on opiate analgesia produced by release of endogenous opiates (front paw footshock induced analgesia) and by intrathecal administration of D-Ala-methionine enkephalinamide, a stable analogue of an endogenous opiate. Additionally, the specificity of proglumide's effect was examined by testing the effect of this drug on various forms of non-opiate analgesia. This series of experiments demonstrate that CCK antagonists can markedly potentiate analgesia induced by endogenous opiates and provide strong support for the hypothesis that endogenous CCK systems can oppose the analgesic effects of opiates. Potentiation of analgesia by CCK receptor blockers appears to be selective for opiate systems since proglumide typically attenuated or had no effect on various forms of non-opiate analgesia. These data suggest that CCK blockers may be clinically useful for enhancing the analgesic effects of procedures such as acupuncture, which may be mediated by release of endogenous opiates.

Analgesia↗
PubMed1990

Chronic administration of cholecystokinin antagonists reverses the enhancement of spinal morphine analgesia induced by acute pretreatment.

The effects of acute and chronic (22 days) treatment with the cholecystokinin (CCK) antagonists proglumide and lorglumide on antinociception induced by intrathecal (i.t.) morphine were determined at weekly intervals with the rat tail-flick assay. On day 1, acute pretreatment with either proglumide (20 ng, i.t.) or lorglumide (7 ng, i.t.) enhanced morphine (1 microgram, i.t.) analgesia compared to saline (1 microliter, i.t.) pretreatment, but this facilitation was absent on days 8 and 15 of CCK antagonist treatment and was replaced by attenuation of opioid antinociception on day 22. Following termination of daily proglumide or lorglumide injections, normal (control) morphine response was observed after pretreatment with either CCK antagonist on days 29 and 36. Weekly co-administration of either drug with morphine had similar effects: opioid antinociception was initially enhanced on day 1, but this amplification was lost by day 8 and remained absent for the duration of the study (i.e., up to day 36). Inhibition of morphine analgesia, however, was not observed with this treatment paradigm. Chronic daily administration of either CCK antagonist alone did not lower nociceptive thresholds; further, normal opioid response was retained throughout the study in saline treated controls receiving morphine weekly. This study demonstrates that whereas acute i.t. administration of CCK antagonists enhances i.t. morphine antinociception, chronic treatment causes loss of facilitation or attenuation of opioid antinociception, suggesting that (1) compensatory alterations in CCK-opioid interactions develop during chronic CCK blockade and (2) CCK antagonists may not be useful adjuncts to opioid analgesics in the management of chronic pain in man.

Analgesia↗
PubMed1987

Regional and cellular heterogeneity of cholecystokinin receptors mediating muscle contraction in the gut.

The contractile action of cholecystokinin (CCK) on smooth muscle of the gut is either direct (gallbladder and gastric fundus) or both direct and neurally mediated (small intestine). These regional differences were used to characterize pharmacologically CCK receptors on smooth muscle cells and neurons of the gastric fundus, gallbladder, and ileum of the guinea pig. In circular and longitudinal ileal smooth muscle, tetrodotoxin was used to separate direct from neurally mediated contractile effects. Cholecystokinin receptors on smooth muscle cells were found in all locations. The muscle cells displayed a decreasing order of sensitivity to the C-terminal octapeptide of cholecystokinin as expressed in the median doses, and to the selective cholecystokinin antagonist, proglumide, as expressed in the inhibitory dissociation constants. The median doses of the octapeptide of cholecystokinin ranged from 5.5 nM in gallbladder muscle to 185 nM in circular ileal muscle; the corresponding inhibitory dissociation constants of proglumide ranged from 180 to 437 microM [corrected]. Cholecystokinin receptors on cholinergic neurons were confined to circular and longitudinal ileal muscle; the neurons were 80-300 times more sensitive to the octapeptide of cholecystokinin (D50's 0.5 and 2.3 nM) than the corresponding muscle cells, and 19-21 times more sensitive to proglumide (inhibitory dissociation constants, 20 microM [corrected]). The results provide clear evidence of cellular heterogeneity of cholecystokinin receptors (i.e., difference in sensitivity between muscle cells and neurons from the same location) as well as regional heterogeneity (i.e., difference in sensitivity between muscle cells from various locations).

Animals↗
PubMed1988

Peptide YY and gallbladder contraction. Studies in vivo and in vitro.

The purpose of this study was to examine the effect of peptide YY on contraction of the gallbladder in vivo and in vitro and on contraction of the sphincter of Oddi in vitro. In conscious dogs that were prepared with strain-gauge force transducers implanted in the gallbladder wall, peptide YY (400 ng/kg, bolus; 800 pmol/kg.h, infusion) did not affect the resting contractile pattern of the gallbladder, nor did it inhibit cholecystokinin-octapeptide (CCK-8)-stimulated gallbladder contraction. In contrast, the cholecystokinin antagonist proglumide (5, 10, 20, 40, or 80 mg/kg), given in vivo, inhibited CCK-8-stimulated gallbladder contraction in a dose-related manner. The highest dose of proglumide (80 mg/kg) completely abolished contraction of the gallbladder stimulated by CCK-8. In vitro studies showed that peptide YY (0.25, 0.5, or 1 microgram/ml) did not affect the resting tension of rabbit gallbladder strips, and it did not inhibit CCK-8-stimulated contraction of gallbladder strips. Proglumide (0.4, 0.8, 1.6, or 3.2 mg/ml) inhibited CCK-8-stimulated tension of gallbladder strips in a dose-related manner. Peptide YY and CCK-8 had no effect on the motility of the canine sphincter of Oddi in vitro, whereas acetylcholine caused contraction and adrenergic agonists caused relaxation. These results suggest that peptide YY and pancreatone (a peptidelike substance, extracted from ileal and colonic mucosa, that inhibits CCK-8-stimulated gallbladder contraction in vivo) do not appear to be identical.

Ampulla of Vater↗
PubMed1993

Cholecystokinin receptors and memory: a radial maze study.

CCK receptor agonists and antagonists have repeatedly been demonstrated to improve and impair, respectively, learning and memory functions. However, all studies to date have exploited avoidance paradigms. In the present study, the effect of some CCK receptor agonists and antagonists on the ability to learn an appetitively motivated task and to influence spatial working memory was investigated. In the first experiment, drugs were given immediately after each training session in the radial maze and the animals were tested, drug-free, during a 2-week period. After the initial treatments with caerulein, an unselective CCK receptor agonist (100 ng/kg SC), the animals were slightly less successful to obtain food pellets during the sessions on the first 2 days; whereas proglumide, an unselective CCK receptor antagonist (1 mg/kg SC) was without any effect. However, on the following days, all the three groups of rats (saline, caerulein, and proglumide) performed in a similar way. In the second experiment, drugs were given before each test session to well-trained animals. Scopolamine (0.15 and 0.3 mg/kg IP), the reference amnestic drug, produced dose-dependent impairment of working memory in the radial maze test. Proglumide (1 and 10 mg/kg SC) and devazepide, (a selective CCK-A receptor antagonist; 0.01 and 1 mg/kg SC), as well as caerulein (0.01, 0.1 and 1 microgram/kg SC) and CCK-4 (a selective CCK-B receptor agonist; 25 and 50 micrograms/kg SC) had no reliable effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2004

Differential contribution of cholecystokinin receptors to stress-induced modulation of seizure and nociception thresholds in mice.

Recent evidence suggest that endogenous cholecystokinin (CCK) has important roles in central responses to stress. CCK receptors are known as functional modulators of opioidergic system with a tonic antiopioid effect in nociceptive pathways. In contrast, CCK receptor ligands are known to induce anticonvulsant effects similar to endogenous opioids. It is not clear whether endogenous CCK may play a role in the anticonvulsant effects of stress, especially in those stressful paradigms that are associated with strong activation of opioid pathways. The present study examined the role of endogenous CCK receptors in acute stress-induced modulation of seizure (clonic seizures induced by pentylenetetrazole) and nociception (tail-flick) thresholds. Acute restraint stress (for 2 h) and prolonged intermittent footshock stress (30 min) both induced opioid-dependent anticonvulsant and antinociceptive effects. While CCK receptor antagonist proglumide (10, 20, or 40 mg/kg) had no effect on seizure or nociception threshold by itself, it inhibited the anticonvulsant effects of both these types of stress while potentiating their antinociceptive effects. Moreover, proglumide exerted a similar inhibition of the anticonvulsant effect and potentiation of the antinociceptive effect of acute morphine at 1 mg/kg. In contrast, brief and continuous footshock stress (3 min) that induced a nonopioid type of antinociception did not increase the seizure threshold. Proglumide pretreatment did not alter any of these effects of brief footshock stress paradigm. The present data suggest that CCK receptors specifically and differentially modulate the opioid-mediated anticonvulsant and antinociceptive effects of acute stress.

Animals↗
PubMed1987

Dissociation of tolerance and dependence to morphine: a possible role for cholecystokinin.

Since cholecystokinin (CCK) has been suggested to be an endogenous opiate antagonist, we tried to evaluate if this peptide could be involved in the development of tolerance to morphine. Naive rats were chronically administered morphine, either alone or concomitantly with proglumide or benzotript, two putative CCK receptor antagonists. Chronic treatments with both CCK antagonists alone were also established. Drugs were administered by the oral route, dissolved in the drinking water. At the end of the chronic treatments, the development of tolerance to morphine was assessed by an evaluation of the analgesic responses evoked by graded doses of acutely injected morphine in the tail-flick and hot plate tests. Proglumide and benzotript were able to inhibit the shift to the right of the dose-response curve for morphine, i.e. they prevented the development of tolerance to morphine-induced analgesia. Chronically given alone, the two CCK antagonists never modified the responses to the acute challenge with morphine. We also determined the development of physical dependence by looking at the withdrawal syndrome precipitated by graded doses of acutely injected naloxone. In these experiments the concomitant treatment with morphine and proglumide or benzotript did not modify the occurrence of dependence. These observations are consistent with the hypothesis of CCK being an endogenous opiate antagonist, involved in the development of tolerance to morphine-induced analgesia but not of dependence. Moreover, tolerance to and dependence on morphine can be pharmacologically dissociated.

Animals↗
PubMed1997

The effect of centrally administered CCK-receptor antagonists on food intake in rats.

Cholecystokinin (CCK) receptors are classified as two subtypes, designated CCK(A) and CCK(B), and both subtypes are found in brain and peripheral tissues of rats. CCK-8 has been shown to act peripherally to reduce meal size, and this satiating action can be blocked by CCK(A)-receptor antagonists. Recent evidence suggests that, in addition to the peripheral action of CCK, central CCK mechanisms may also be involved in satiety. Central administration of proglumide, a mixed CCK-receptor antagonist (CCK(A) > CCK(B)) has been shown to increase food intake and block the satiating effect of peripherally administered CCK-8 (15). In an attempt to replicate and extend these results, rats were given injections of proglumide or selective CCK-receptor antagonists into the lateral ventricle prior to a peripheral injection of CCK-8 or saline. Only proglumide stimulated an increase in 30-min test meal intake and attenuated the satiating effect of CCK-8. Two selective CCK(A)-receptor antagonists, lorglumide and devazepide, did not increase intake significantly when given alone, and they did not attenuate the effect of peripherally administered CCK-8. The selective CCK(B)-receptor antagonist, L365,260, reduced intake at all doses tested except the lowest. The lowest dose did not increase intake when given alone and did not attenuate the inhibitory effect of CCK on test-meal intake. Finally, a combination of devazepide and L365,260 did not increase intake or block the effect of peripherally administered CCK-8. These results suggest that CCK released by neurons in the brain and acting on central CCK(A)- and CCK(B)-receptors is not necessary for the control of meal size or for the satiating effect of peripherally administered CCK-8 in rats under our experimental conditions.

Animals↗
PubMed2002

Modulation of cholestasis-induced antinociception by CCK receptor agonists and antagonists.

Acute cholestasis is associated with increased activity of the endogenous opioid system. Agonists and antagonists of cholecystokinin (CCK) receptors are known to modulate opioid-induced antinociception. In the present study, the effect of the CCK receptor agonist caerulein and the antagonist proglumide on antinociception induced during acute cholestasis was investigated in rats using the tail-flick test. A significant increase in nociception threshold was observed in bile duct ligated (BDL) rats compared to sham-operated controls that was maximum on day 7 after the operation and decreased thereafter. Proglumide (40 mg/kg, i.p.) did not affect nociception in unoperated and sham-operated animals, but exerted a significant potentiation of antinociception in cholestatic rats in a way similar to its potentiation effect on unoperated morphine-treated (2 mg/kg, s.c.) animals. Caerulein (0.005, 0.001, 0.01 and 0.02 mg/kg, s.c.), which did not change nociception per se or in sham-operated animals, also significantly potentiated the antinociception in BDL rats as well as in morphine-treated unoperated controls. Caerulein-induced potentiation of antinociception in BDL animals was completely reversed by proglumide pretreatment. Our findings show that, in cholestatic animals, modulation of nociception by the CCK system is different from normal subjects and resembles the state observable in morphine-administered subjects.

Animals↗
PubMed1996

Gastrin and gastrin receptor antagonists bind to both N- and C-terminal halves of the 78 kDa gastrin-binding protein.

A 78 kDa gastrin-binding protein (GBP) has previously been identified as the target of the anti-proliferative effects of non-selective gastrin/cholecystokinin receptor antagonists on colorectal carcinoma cell lines. The GBP was related in sequence to a family of fatty acid oxidation enzymes possessing enoyl CoA hydratase and 3-hydroxyacyl CoA dehydrogenase activity. This study aims to define the binding site for gastrin and gastrin antagonists in greater detail. The N- and C-terminal halves of the porcine GBP were expressed independently as glutathione S-transferase fusion proteins in E. coli. Affinities of gastrin and gastrin antagonists for the fusion proteins were measured by competition for 125I-[Nle15]-gastrin binding in a covalent cross-linking assay. The N- and C-terminal fusion proteins bound gastrin with affinities of 9.9 +/- 6.1 and 71 +/- 48 microM, respectively (n = 3). These values were 40-fold and 300-fold lower than the affinity of the full-length GBP for gastrin (0.23 +/- 0.15 microM). In contrast, the affinities of the N- and C-terminal halves for the antagonists proglumide (22 +/- 13 and 10 +/- 4 mM, respectively) and benzotript (350 +/- 90 and 400 +/- 160 micro M, respectively) were similar to each other and to the affinities of proglumide and benzotript for the full-length GBP (5.1 +/- 3.6 mM and 200 +/- 120 microM, respectively). It is concluded that proglumide and benzotript bind independently to both the hydratase and dehydrogenase active sites of the GBP, while a single molecule of gastrin may bind simultaneously to both active sites. A model is proposed which is consistent with these data, and which will assist in the development of more potent and selective GBP antagonists.

Animals↗
PubMed2000

Antinociceptive effect of intracerebroventricular administration of cholecystokinin antagonist in nerve-ligated mice.

In the present study we investigated the effects of intracerebroventricular injection of caerulein, the cholecystoki nin receptor agonist and proglumide, the receptor antagonist on morphine response in the sciatic nerve ligation in mice. Subcutaneous administration of morphine induced antinociception in the both intact and ligated mice, however, the response of the opioid was lower in the ligated mice as compared with the intact animals. Caerulein induced antinociception in the non-ligated but not in the nerve-ligated animals. Combination of caerulein with morphine elicited higher response in ligated animals, however, the response induced in ligated animals was much more prominent. Proglumide alone did not elicit any response in both animal groups. The antagonist decreased the response of caerulein in the nonligated mice. Low doses of proglumide in the combination with caerulein induced antinociception in the ligated mice. We conclude that cholecystokinin receptor mechanism(s) may alter morphine resistance induced by nerve ligation.

Analgesics, Opioid↗
PubMed1989

Effect of CCK antagonists CR 1409 and CR 1505 on rat pancreatic exocrine secretion in vivo.

The action of cholecystokinin (CCK) antagonists CR 1409 and CR 1505 on pancreatic exocrine secretion stimulated by exogenous and endogenous CCK was studied in vivo in anesthetized rats, and compared with proglumide. Intravenous administration of CR 1409 and CR 1505 in graded doses between 0.04 and 25 mg/kg/h resulted in a dose-dependent inhibition in pancreatic juice volume and amylase output stimulated by intravenous infusion of CCK-8 in a dose of 0.06 microgram/kg/h. CR 1409 is 1,000 times and CR 1505 is 267 times more potent than proglumide, based on the ED50 (effective dose for half-maximal inhibition) for CCK-8-stimulated amylase secretion. Intraduodenal administration of casein in a dose of 400 mg/h caused significant increases in plasma CCK concentration and pancreatic secretion of juice volume and outputs of amylase and trypsin. Both CR 1409 and CR 1505 in a dose of 5 mg/kg/h suppressed the increases in pancreatic juice volume and both amylase and trypsin outputs induced by casein given intraduodenally. These results indicate that CCK antagonists including CR 1409, CR 1505, and proglumide inhibit pancreatic exocrine secretion stimulated by not only exogenous, but also endogenous CCK in rats.

Animals↗
PubMed1991

Synthetic CCK8 analogs with antagonist activity on pancreatic receptors: in vivo study in the rat, compared to non-peptidic antagonists.

The cholecystokinin octapeptide (CCK8)-derived synthetic peptides Boc-Tyr(SO3H)-Nle-Gly-DTrp-Nle-Asp-O-CH2-CH2-C6H5 (JMV179) and Boc-Tyr(SO3H)-Nle-Gly-DTrp-Nle-Asp-NH-CH2-CH2-C6H5 (JMV167) are antagonists of peripheral cholecystokinin (CCK) receptors in vitro. In the present study, antagonist activity of these peptides was studied on rat pancreatic secretion in vivo, and compared to those of other peptidic molecules and to the non-peptidic antagonists L364718, D-, L-, DL-lorglumide, and proglumide. The decreasing order of antagonist potencies on amylase release in vitro was L364718 greater than JMV179 greater than lorglumide greater than JMV167 greater than proglumide; JMV179 was 25 times less potent than L364718 and 300 times more potent than JMV167. The decreasing order of antagonist potencies on protein output in pancreatic juice in vivo was L364718 greater than JMV167 greater than JMV179 greater than lorglumide greater than proglumide; JMV167 was two times more potent than JMV179 and only 8 times less potent than L364718. Increased potency of JMV167, relative to JMV179 under in vivo conditions, is probably due to the slower rate of catabolism of the phenylethylamide group, relative to the phenylethylester group, since the metabolite issued from hydrolysis of the ester bond was totally inactive. This study shows that it is possible to obtain peptidic CCK antagonists, which are active and potent in vivo, and provides a quantitative measurement of potency changes occurring in vivo for several peptidic and non-peptidic antagonists.

Amino Acid Sequence↗