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Ruud A Woutersen - One of the best experts on this subject based on the ideXlab platform.
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effects of Cholecystokinin and bombesin on development of azaserine induced pancreatic tumours in rats modulation by the Cholecystokinin receptor antagonist lorglumide
Carcinogenesis, 1992Co-Authors: M Meijers, Lucio Claudio Rovati, C B H W Lamers, J. B. M. J. Jansen, M J Appel, A Van Garderenhoetmer, Ruud A WoutersenAbstract:: Cholecystokinin and bombesin have been shown to promote pancreatic growth and development of azaserine-induced acidophilic atypical acinar cell nodules in rat pancreas after treatment for 16 weeks. Lorglumide, a specific Cholecystokinin receptor antagonist, inhibited the stimulating effect of Cholecystokinin, but not of bombesin. The present study was carried out to determine effects of Cholecystokinin and bombesin, alone and in combination with lorglumide, on pancreatic growth and carcinogenesis after chronic treatment. The animals were killed 8 months after the start of treatment. Growth of the pancreas and the development of acidophilic atypical acinar cell nodules in exocrine pancreas was enhanced significantly by both Cholecystokinin and bombesin, but the number of carcinomas was increased only by bombesin. Lorglumide inhibited the effects of Cholecystokinin on both pancreatic growth and on the development of acidophilic nodules. The effects of bombesin on pancreatic growth and development of pancreatic lesions, except for adenomas, were not inhibited by lorglumide.
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role of Cholecystokinin in dietary fat promoted azaserine induced pancreatic carcinogenesis in rats
British Journal of Cancer, 1992Co-Authors: M J Appel, Lucio Claudio Rovati, C B H W Lamers, J. B. M. J. Jansen, M Meijers, A Van Garderenhoetmer, D Sprijmooij, Ruud A WoutersenAbstract:The role of Cholecystokinin in dietary fat-promoted pancreatic carcinogenesis was investigated in azaserine-treated rats, using lorglumide, a highly specific Cholecystokinin-receptor antagonist. The animals were killed 8 months after the start of treatment. Cholecystokinin, but not dietary unsaturated fat, increased pancreatic weight. Rats treated with Cholecystokinin developed more acidophilic atypical acinar cell nodules, adenomas and adenocarcinomas than control animals. Rats maintained on the high-fat diet developed significantly more adenomas and adenocarcinomas than controls given a diet low in unsaturated fat. Lorglumide largely inhibited the enhancing effect of Cholecystokinin, but not of dietary fat, on pancreatic carcinogenesis indicating that it is unlikely that the promoting effect of dietary unsaturated fat on pancreatic carcinogenesis is mediated via Cholecystokinin.
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Cholecystokinin-Receptor Antagonists in Experimental Pancreatic Tumor Growth
Cholecystokinin Antagonists in Gastroenterology, 1991Co-Authors: C. B. H. Lamers, B R Douglas, J. B. M. J. Jansen, Ruud A WoutersenAbstract:Cholecystokinin belongs together with gastrin and secretin to the classical gut hormones [1]. Cholecystokinin is produced by the I cells in the upper small intestinal mucosa and is released into the circulation in response to ingestion of nutrients or infusion of the neurotransmitter bombesin/gastrin releasing peptide. The polypeptide hormone is named Cholecystokinin because of its property to stimulate gallbladder contraction. In addition to its gallbladder-contracting property, Cholecystokinin has been shown to be a potent stimulus of pancreatic growth and pancreatic enzyme and hormone secretion, to affect motility of the gastrointestinal tract, and to play a role in the regulation of satiety. Because of its pancreatic growth promoting action, Cholecystokinin has been studied in pancreatic carcinogenesis [2–4]. The recent development of highly effective and specific Cholecystokinin-receptor antagonists has enabled to delineate the various actions of Cholecystokinin in great detail [5,6]. Two types of Cholecystokinin-receptor antagonists can be used for in vivo studies, glutaramic derivates (proglumide, lorglumide, loxiglumide) and non-peptide compounds (asperlicin, L-364718). Most in vivo studies have been performed using the glutaramic derivates lorglumide (CR-1409) and loxiglumide (CR-1505) and the non-peptide antagonist L-364718 (MK-329). Studies on the role of Cholecystokinin on gastrointestinal tumor growth have been concentrated on the role of Cholecystokinin in pancreatic cancer.
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Cholecystokinin and gastrointestinal cancer.
The Journal of Steroid Biochemistry and Molecular Biology, 1990Co-Authors: Cornelis B.h.w. Lamers, J. B. M. J. Jansen, Ruud A WoutersenAbstract:The gut hormone Cholecystokinin exerts various actions on the gastrointestinal tract, including the regulation of growth. The hormone has been reported to induce hypertrophy and hyperplasia of the pancreas and to enhance chemically-induced pancreatic carcinogenesis in animals. Stimulation of endogenous Cholecystokinin secretion through the induction of deficiency of intraintestinal proteases and bile salts by trypsin-inhibiting nutrients, bile salt-binding drugs or surgical intervention is also capable of stimulating growth and tumour development in the rat. In man, factors suggested to increase the risk of pancreatic cancer, such as a high-fat and high-protein diet or gastrectomy, are known to stimulate plasma Cholecystokinin secretion. Receptors for Cholecystokinin have been demonstrated on human pancreatic adenocarcinomas, and Cholecystokinin has been demonstrated to enhance the growth of xenografted pancreatic cancer and to inhibit growth of gastric and bile duct cancer. The recently developed Cholecystokinin-receptor antagonists inhibit not only pancreatic growth but also pancreatic carcinogenesis in animals. These new drugs may be valuable new tools for inhibiting pancreatic cancer growth in humans.
Antonella Ursini - One of the best experts on this subject based on the ideXlab platform.
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1-Phenyl-4(1H)-quinazolinones and 2,3-dihydro-1-phenyl-4(1H)-quinazolinones as potential Cholecystokinin receptor ligands
Journal of Heterocyclic Chemistry, 1996Co-Authors: Giorgio Pentassuglia, Barbara Bertani, Daniele Donati, Antonella UrsiniAbstract:A series of new l-phenyl-4(1H)-quinazolinones and 2,3-dihydro-1-phenyl-4(1H)-quinazolinones were synthesized and tested as Cholecystokinin receptor ligands. All the compounds showed moderate affinity and 1-phenyl-4(1H)-quinazolinones resulted more effective towards the Cholecystokinin-B receptor, meanwhile the dihydro derivatives were generally more effective towards the Cholecystokinin-A receptor.
Howard L. Fields - One of the best experts on this subject based on the ideXlab platform.
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a locus and mechanism of action for associative morphine tolerance
Nature Neuroscience, 2000Co-Authors: Jennifer M Mitchell, Allan I Basbaum, Howard L. FieldsAbstract:Repeated administration of an opioid in the presence of specific environmental cues can induce tolerance specific to that setting (associative tolerance). Prolonged or repeated administration of an opioid without consistent contextual pairing yields non-associative tolerance. Here we demonstrate that Cholecystokinin acting at the Cholecystokinin-B receptor is required for associative but not non-associative morphine tolerance. Morphine given in the morphine-associated context increased Fos-like immunoreactivity in the lateral amygdala and hippocampal area CA1. Microinjection of the Cholecystokinin B antagonist L-365,260 into the amygdala blocked associative tolerance. These results indicate that Cholecystokinin acting in the amygdala is necessary for associative tolerance to morphine's analgesic effect.
Christian Broberger - One of the best experts on this subject based on the ideXlab platform.
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Modulation of motor behaviour by NMDA- and Cholecystokinin-antagonism
Amino Acids, 1998Co-Authors: Christian Broberger, David Blacker, Sven-ove Ögren, L. Giménez-llort, M. Herrera-marschitz, T. HükfeltAbstract:Motor behaviour relies on complex neurochemical interactions in the basal ganglia, in particular the striatum. Antagonistic influences in this region are exerted by afferent projections from, on the one hand, the ventral mesencephalon, utilizing dopamine as a transmitter, and, on the other hand, from the cerebral cortex, signalling by the excitatory amino acid glutamate. The activity in both these neuronal populations appears to be regulated by the neuropeptide Cholecystokinin. This article concentrates on interactions between Cholecystokinin and glutamate, summarizing some recent morphological, biochemical and behavioural findings. It is suggested that Cholecystokinin, acting via the CholecystokininB receptor, potentiates the glutamatergic excitatory input to the striatum.
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Cholecystokinin b receptor antagonists enhance the locomotor response to the n methyl d aspartate antagonists phencyclidine and dizocilpine maleate
Neuroscience, 1997Co-Authors: David Blacker, Christian Broberger, Sven-ove Ögren, Tomas HokfeltAbstract:Abstract The Cholecystokinin antagonists L-740,093, L-365,260, LY-288513 and CI988, which are all selective for the Cholecystokinin B receptor subtype, were examined for their ability to modulate locomotor activity induced by the non-competitive N -methyl- d -aspartate receptor antagonists phencyclidine and dizocilpine maleate (MK-801) in habituated rats. It was found that the locomotor effects (motility, locomotion) produced by subcutaneous administration of phencyclidine (2 mg/kg) were significantly potentiated by intraperitoneal (i.p.) administration of L-740,093 (1 mg/kg), L-365,260 (10 mg/kg), LY-288513 (10 mg/kg), but not CI-988 (10 mg/kg). Locomotor activity induced by subcutaneous administration of MK-801 (0.15 mg/kg) was potentiated by intraperitoneal L-740,093 (0.3, 1 and 3 mg/kg). L-740,093, L-365,260, LY-288513 and CI-988 administered alone did not alter spontaneous locomotor activity (motility) as compared to vehicle/saline controls. However, when these antagonists were administered to naive, unhabituated rats, L-365,260 and LY-288513 caused a significant reduction in motility compared to the vehicle control. These findings suggest that, although Cholecystokinin may be involved in exploratory behaviour exhibited by rats in a novel environment (unhabituated rats), its role is negligible in rats subjected to a familiar environment (habituated rats). Furthermore, these results support the interpretation that Cholecystokinin has a suppressant effect on locomotion elicited by phencyclidine and MK-801, and that this inhibitory action of Cholecystokinin is mediated via the Cholecystokinin B receptor, since it can be eliminated by administration of Cholecystokinin B antagonists. It is suggested that the site of action of the Cholecystokinin B receptors involves mainly the Cholecystokinin/glutamate projection from the cortex to the anterior nucleus accumbens and/or striatum. Finally, the present study provides two examples of endogenous release of a neuropeptide resulting in behavioural consequences.
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marked increase in Cholecystokinin b receptor messenger rna levels in rat dorsal root ganglia after peripheral axotomy
Neuroscience, 1993Co-Authors: Xu Zhang, A Dagerlind, M N Castel, Christian Broberger, Z Wiesenfeldhallin, Robert Elde, Ho T KfeltAbstract:Abstract It is now well established that the expression of peptides in rat primary sensory neurons is dramatically changed in response to peripheral nerve injury. Thus, as first shown by Jessell et al. 15 peripheral axotomy causes a decrease in substance P levels in the dorsal horn of the corresponding spinal cord segments, and this is due to down-regulation of peptide synthesis in dorsal root ganglion neurons. 22 In contrast, other peptides such as vasoactive intestinal polypeptide and peptide histidine isoleucine, 27 galanin 12 and neuropeptide Y 32 are all markedly upregulated in the rat L4 and L5 dorsal root ganglia after sciatic nerve sectioning. The levels of another peptide, Cholecystokinin and its messenger RNA are normally very low or undectable in rat primary sensory neurons, 5,20,24,25,26 but after peripheral axotomy approximately 30% of the ganglion neurons express Cholecystokinin messenger RNA. 30 During the last few years a number of peptide receptors have been cloned, and they all belong to the family of G-protein coupled receptors with seven membrane spanning segments, 21 among them the two Cholecystokinin receptors Cholecystokinin A and Cholecystokinin B . 17,23,34 Ghilardi et al . 11 have recently described presence of Cholecystokinin B binding sites in rat dorsal root ganglia neurons. In the present study we report that the messenger RNA for the Cholecystokinin B receptor is present at very low levels in normal dorsal root ganglia of the rat, but axotomy causes a very marked increase in the number of sensory neurons of all sizes expressing Cholecystokinin B receptor messenger RNA, suggesting an increased sensitivity to Cholecystokinin for many primary sensory neurons of different modalities after lesion.
J. B. M. J. Jansen - One of the best experts on this subject based on the ideXlab platform.
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effects of Cholecystokinin and bombesin on development of azaserine induced pancreatic tumours in rats modulation by the Cholecystokinin receptor antagonist lorglumide
Carcinogenesis, 1992Co-Authors: M Meijers, Lucio Claudio Rovati, C B H W Lamers, J. B. M. J. Jansen, M J Appel, A Van Garderenhoetmer, Ruud A WoutersenAbstract:: Cholecystokinin and bombesin have been shown to promote pancreatic growth and development of azaserine-induced acidophilic atypical acinar cell nodules in rat pancreas after treatment for 16 weeks. Lorglumide, a specific Cholecystokinin receptor antagonist, inhibited the stimulating effect of Cholecystokinin, but not of bombesin. The present study was carried out to determine effects of Cholecystokinin and bombesin, alone and in combination with lorglumide, on pancreatic growth and carcinogenesis after chronic treatment. The animals were killed 8 months after the start of treatment. Growth of the pancreas and the development of acidophilic atypical acinar cell nodules in exocrine pancreas was enhanced significantly by both Cholecystokinin and bombesin, but the number of carcinomas was increased only by bombesin. Lorglumide inhibited the effects of Cholecystokinin on both pancreatic growth and on the development of acidophilic nodules. The effects of bombesin on pancreatic growth and development of pancreatic lesions, except for adenomas, were not inhibited by lorglumide.
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role of Cholecystokinin in dietary fat promoted azaserine induced pancreatic carcinogenesis in rats
British Journal of Cancer, 1992Co-Authors: M J Appel, Lucio Claudio Rovati, C B H W Lamers, J. B. M. J. Jansen, M Meijers, A Van Garderenhoetmer, D Sprijmooij, Ruud A WoutersenAbstract:The role of Cholecystokinin in dietary fat-promoted pancreatic carcinogenesis was investigated in azaserine-treated rats, using lorglumide, a highly specific Cholecystokinin-receptor antagonist. The animals were killed 8 months after the start of treatment. Cholecystokinin, but not dietary unsaturated fat, increased pancreatic weight. Rats treated with Cholecystokinin developed more acidophilic atypical acinar cell nodules, adenomas and adenocarcinomas than control animals. Rats maintained on the high-fat diet developed significantly more adenomas and adenocarcinomas than controls given a diet low in unsaturated fat. Lorglumide largely inhibited the enhancing effect of Cholecystokinin, but not of dietary fat, on pancreatic carcinogenesis indicating that it is unlikely that the promoting effect of dietary unsaturated fat on pancreatic carcinogenesis is mediated via Cholecystokinin.
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Cholecystokinin-Receptor Antagonists in Experimental Pancreatic Tumor Growth
Cholecystokinin Antagonists in Gastroenterology, 1991Co-Authors: C. B. H. Lamers, B R Douglas, J. B. M. J. Jansen, Ruud A WoutersenAbstract:Cholecystokinin belongs together with gastrin and secretin to the classical gut hormones [1]. Cholecystokinin is produced by the I cells in the upper small intestinal mucosa and is released into the circulation in response to ingestion of nutrients or infusion of the neurotransmitter bombesin/gastrin releasing peptide. The polypeptide hormone is named Cholecystokinin because of its property to stimulate gallbladder contraction. In addition to its gallbladder-contracting property, Cholecystokinin has been shown to be a potent stimulus of pancreatic growth and pancreatic enzyme and hormone secretion, to affect motility of the gastrointestinal tract, and to play a role in the regulation of satiety. Because of its pancreatic growth promoting action, Cholecystokinin has been studied in pancreatic carcinogenesis [2–4]. The recent development of highly effective and specific Cholecystokinin-receptor antagonists has enabled to delineate the various actions of Cholecystokinin in great detail [5,6]. Two types of Cholecystokinin-receptor antagonists can be used for in vivo studies, glutaramic derivates (proglumide, lorglumide, loxiglumide) and non-peptide compounds (asperlicin, L-364718). Most in vivo studies have been performed using the glutaramic derivates lorglumide (CR-1409) and loxiglumide (CR-1505) and the non-peptide antagonist L-364718 (MK-329). Studies on the role of Cholecystokinin on gastrointestinal tumor growth have been concentrated on the role of Cholecystokinin in pancreatic cancer.
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Cholecystokinin and gastrointestinal cancer.
The Journal of Steroid Biochemistry and Molecular Biology, 1990Co-Authors: Cornelis B.h.w. Lamers, J. B. M. J. Jansen, Ruud A WoutersenAbstract:The gut hormone Cholecystokinin exerts various actions on the gastrointestinal tract, including the regulation of growth. The hormone has been reported to induce hypertrophy and hyperplasia of the pancreas and to enhance chemically-induced pancreatic carcinogenesis in animals. Stimulation of endogenous Cholecystokinin secretion through the induction of deficiency of intraintestinal proteases and bile salts by trypsin-inhibiting nutrients, bile salt-binding drugs or surgical intervention is also capable of stimulating growth and tumour development in the rat. In man, factors suggested to increase the risk of pancreatic cancer, such as a high-fat and high-protein diet or gastrectomy, are known to stimulate plasma Cholecystokinin secretion. Receptors for Cholecystokinin have been demonstrated on human pancreatic adenocarcinomas, and Cholecystokinin has been demonstrated to enhance the growth of xenografted pancreatic cancer and to inhibit growth of gastric and bile duct cancer. The recently developed Cholecystokinin-receptor antagonists inhibit not only pancreatic growth but also pancreatic carcinogenesis in animals. These new drugs may be valuable new tools for inhibiting pancreatic cancer growth in humans.