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PubMed1991

Analgesia produced by pituitary ACTH and dopaminergic transmission in the arcuate.

Analgesia (NAA) caused by nonacupuncture point (abdominal muscle) stimulation after lesioning the analgesia inhibitory system (AIS) or treating the subject with proglumide was abolished by hypophysectomy or adrenalectomy. The final sector of the NAA afferent pathway from the nonacupuncture point to the pituitary gland and the initial sector of the descending pain inhibitory system were found in the anterior and posterior arcuate nucleus (A-HARN and P-HARN), respectively. Analgesia caused by ACTH microinjected into the P-HARN disappeared after denervation of the A-HARN, but that caused by dopamine did not. Firing rates of P-HARN neurons were increased by nonacupuncture point simulation (NAPS) after lesion of the AIS or treatment with proglumide. The NAPS responsive neurons also responded to ultramicroinjected dopamine, but not to ultramicroinjected ACTH. Both NAA and NAPS responsive neuron activity that were abolished by hypophysectomy were restored by concurrent application of NAPS and intraperitoneal ACTH. Reduction of sodium ions due to adrenalectomy was found to abolish NAA. It was concluded that NAA production involves dopaminergic transmission in the HARN and ACTH acting presynaptically on this transmission.

Adrenal Glands↗
PubMed2004

Involvement of cholecystokinin in the opioid tolerance induced by dipyrone (metamizol) microinjections into the periaqueductal gray matter of rats.

The analgesic effect of non-steroidal anti-inflammatory drugs (NSAIDs) is partly due to an action upon the periaqueductal gray matter (PAG), which triggers the descending pain control system and thus inhibits nociceptive transmission. This action of NSAIDs engages endogenous opioids at the PAG, the nucleus raphe magnus and the spinal cord. Repeated administration of NSAIDs such as dipyrone (metamizol) and acetylsalicylate thus induces tolerance to these compounds and cross-tolerance to morphine. Since cholecystokinin plays a key role in opioid tolerance, the present study in rats investigated whether PAG cholecystokinin is also responsible for tolerance to PAG-microinjected dipyrone. Microinjection of cholecystokinin (1 ng/0.5 microl) into PAG blocked the antinociceptive effect of a subsequent microinjection of dipyrone (150 microg/0.5 microl) into the same site, as evaluated by the tail flick and hot plate tests. Microinjection of proglumide (0.4 microg/0.5 microl), a non-selective cholecystokinin antagonist, into PAG prevented the development of tolerance to subsequent microinjections of dipyrone, as well as cross-tolerance to microinjection of morphine (5 microg/0.5 microl) into the same site. In rats tolerant to PAG dipyrone, a PAG microinjection of proglumide restored the antinociceptive effect of a subsequent microinjection of dipyrone or morphine. These results suggest that PAG-microinjected dipyrone triggers and/or potentiates local opioidergic circuits leading to descending inhibition of nociception, on the one hand, and to a local antiopioid action by cholecystokinin, on the other. Reiteration of these events would then result in an enhancement of cholecystokinin's antiopioid action and thus tolerance to opioids and dipyrone in the PAG.

Analgesics, Opioid↗
PubMed2006

Involvement of cholecystokinin in peripheral nociceptive sensitization during diabetes in rats as revealed by the formalin response.

The possible pronociceptive role of peripheral cholecystokinin (CCK-8) as well as CCK(A) and CCK(B) receptors in diabetic rats was assessed. Subcutaneous injection of 0.5% formalin induced a greater nociceptive behavior in diabetic than in non-diabetic rats. Moreover, local peripheral injection of CCK-8 (0.1-100 microg) significantly increased 0.5% formalin-induced nociceptive activity in diabetic, but not in non-diabetic, rats. This effect was restricted to the formalin-injected paw as administration of CCK-8 into the contralateral paw was ineffective. Local peripheral administration of CCK-8, in the absence of formalin injection, produced a low level of, but significant increase in, flinching behavior in diabetic compared to non-diabetic rats. In addition, local peripheral administration of the non-selective CCK receptor antagonist proglumide (1-100 microg), CCK(A) receptor antagonist lorglumide (0.1-100 microg) or CCK(B) receptor antagonist CR-2945 (0.1-100 microg), but not vehicle or contralateral administration of CCK receptor antagonists, significantly reduced 0.5% formalin-induced flinching in diabetic rats. CR-2945 was the most effective drug in this condition. These effects were not observed in non-diabetic rats. The local peripheral pronociceptive effect of CCK-8 (100 microg) was significantly reduced by proglumide (100 microg), lorglumide (100 microg), and CR-2945 (100 microg). Results suggest that diabetes-induced peripheral sensitization could be due to a local peripheral release of CCK-8, which in turn would act on CCK(B), mainly but also in CCK(A), receptors located on the primary afferent neurons.

Animals↗
PubMed1995

Early signalling mechanism in colonic epithelial cell response to gastrin.

The hormone gastrin exerts a growth-promoting effect on gastrointestinal cells. The molecular mechanisms by which colonic epithelial cells respond to gastrin are still poorly understood. In this study, we demonstrate a novel feature of the action of gastrin on normal colonic cells, namely the rapid phosphorylation on tyrosine of phospholipase C gamma 1 (PLC gamma 1). Tyrosine phosphorylation of PLC gamma 1, elicited by gastrin, was transient, concentration-dependent, and was abrogated by pretreating the colonic cells with the gastrin-receptor antagonist proglumide, the tyrosine kinase inhibitor genistein, and by removal of the tyrosine phosphatase inhibitor orthovanadate from the isolation buffer. Tyrosine phosphorylation of PLC gamma 1 correlated with the time- and concentration-dependent decrease in the mass of membrane phosphatidylinositol 4,5-bisphosphate (PIP2) and the increase in the epithelial concentration of inositol 1,4,5-trisphosphate (IP3). Likewise, the stimulated increase in IP3 was also prevented by proglumide and genistein. Gastrin induced a definite but transient increase in the intracellular concentration of free Ca2+ [Ca2+]i, and increased membrane-translocation of immunoreactive alpha- and beta-protein kinase C. The data thus indicate that gastrin elicits at least one signalling cascade, through rapid tyrosine phosphorylation of PLC gamma 1, leading to the activation of a PIP2-specific PLC pathway.

Animals↗
PubMed1994

Antiproliferative gastrin/cholecystokinin receptor antagonists target the 78-kDa gastrin-binding protein.

Inhibition of colon carcinoma cell growth by the nonselective gastrin/cholecystokinin (CCK) receptor antagonists proglumide and benzotript provided evidence that gastrin functions as an autocrine growth factor. However, the molecular properties of the receptor mediating the antagonist effects have not been identified. A 78-kDa gastrin-binding protein (GBP), the sequence of which is related to the family of enzymes possessing enoyl-CoA hydratase and 3-hydroxyacyl-CoA dehydrogenase activities, has been previously purified from porcine gastric mucosal membranes. I now report that covalent cross-linking of 125I-labeled [Nle15]gastrin2,17 to the 78-kDa GBP is inhibited by crotonyl-CoA and by acetoacetyl-CoA. Gastrin, CCK, and their analogues also inhibit cross-linking, and the spectrum of analogue affinities correlates better with the values previously reported for binding to the gastrin/CCK-C receptor than with the values reported for binding to either the CCK-A or the gastrin/CCK-B receptor. Cross-linking is also inhibited by proglumide and benzotript, but no inhibition is seen with either the CCK-A receptor-selective antagonist L364,718 or the gastrin/CCK-B receptor-selective antagonist L365,260. The affinities of antagonists for the GBP correlate well with their affinities for the gastrin/CCK-C receptor and with their potencies for inhibition of colon carcinoma cell growth. I conclude that the 78-kDa gastrin-binding protein is (i) a member of the hydratase/dehydrogenase family of fatty acid oxidation enzymes, (ii) the gastrin/CCK-C receptor, and (iii) the target for the antiproliferative action of two gastrin/CCK receptor antagonists.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed1992

Peripheral 2-hydroxy-saclofen-sensitive GABA-B receptors mediate both vagal-dependent and vagal-independent acid secretory responses in rats.

1. The present study investigates the effects of peripherally administered baclofen on gastric acid secretion from the perfused stomach of anaesthetized rats. 2. Intravenous (i.v.) baclofen caused a marked dose-dependent increase in acid secretion which was antagonized by i.v. 2-hydroxy-saclofen, whereas intracerebroventricular (i.c.v.) 2-hydroxy-saclofen and i.c.v. or i.v. phaclofen and bicuculline were ineffective. In addition, 2-hydroxy-saclofen did not affect acid hypersecretion stimulated by histamine. 3. The secretagogue action of baclofen was fully prevented by cimetidine, but only partially attenuated by atropine, proglumide or bilateral cervical vagotomy. Moreover, the vagotomy-resistant excitatory effect of baclofen was abolished by 2-hydroxy-saclofen or cimetidine, but not by atropine or proglumide. 4. In vagotomized rats whose gastric secretion was maximally increased by electrical stimulation of the left vagus nerve, i.v. injection of baclofen further potentiated acid output, this action being prevented by cimetidine. 5. Taken together, the present results provide evidence that peripheral GABA-B receptors mediate the gastric hypersecretory effect of parenterally administered baclofen to anaesthetized rats, and suggest that both vagal cholinergic and extravagal pathways are involved in the stimulant effect.

Animals↗
PubMed2005

Cholecystokinin octapeptide improves cardiac function by activating cholecystokinin octapeptide receptor in endotoxic shock rats.

AIM: To explore the effect of sulfated cholecystokinin octapeptide (sCCK-8) on cardiac functions and its receptor mechanism in endotoxic shock (ES) rats. METHODS: The changes of the mean arterial pressure (MAP), heart rate (HR), the left ventricular pressure (LVP) and the maximal/minimum rate of LVP (+/-LVdp/dt(max))) were measured by using physiological record instrument in eight groups of rats. The expression of cholecystokinin-A receptor (CCK-AR) and cholecystokinin-B receptor (CCK-BR) mRNA of myocardium in ES rats was examined by reverse transcription polymerase chain reaction (RT-PCR). RESULTS: (1) Low doses of sCCK-8 (0.4 microg/kg) caused tachycardia (441+/-27, normal control 391+/-22 s/min) and slight increase in MAP, LVP and +/-LVdp/dt(max) (16.96+/-1.79, 18.21+/-1.69 and +768.85+/-31.28/-565.04+/-27.71 kPa, respectively, all P<0.01), while medium doses (4.0 microg/kg) and high doses of sCCK-8 (40 microg/kg) elicited bradycardia and marked increase in MAP, LVP and +/-LVdp/dt(max) (17.29+/-1.63, 19.46+/-2.57 and +831.46+/-22.57/-606.08 +/-31.32; 17.46+/-1.08, 19.83+/-2.91 and +914.52+/-35.95/-639.15+/-30.23 kPa, respectively, all P<0.01). Proglumide (1.0 mg/kg), a nonselective antagonist of CCK-receptor (CCK-R), significantly inhibited the pressor effects of sCCK-8 (15.96+/-1.38, 17.36+/-0.66 and +748.18+/-19.29/-512.12+/-14.39 kPa, respectively, all P<0.01), whilst reversing the bradycardiac responses. (2) High doses of LPS (8 mg/kg) elicited marked decrease in MAP, LVP and +/-LVdp/dt(max). (7.16+/-0.59, 7.6+/-0.68 and +298.01+/-25.52/-166.96+/-19.25 kPa, respectively, all P<0.01). Pretreatment with sCCK-8 (40 microg/kg) could reverse the decline of cardiac functions (10.71+/-0.45, 11.7+/-1.26 and +446.04+/-67.18/-347.90+/-36.98 kPa, respectively, all P<0.01), while proglumide could cause further decline of cardiac function in ES rats (4.71+/-0.67, 5.58+/-1.25 and +226.48+/-15.84/-142.83+/-20.23 kPa, respectively, all P<0.01). (3) CCK-A/BR mRNAs were expressed in myocardium of control rats. Gene expression of CCK-AR and CCK-BR significantly increased in myocardium of ES rats. The increase of CCK-AR mRNA induced by LPS began at 0.5 h, peaked at 2 h, kept a high level at 6 h and declined at 12 h, respectively. Similar to CCK-AR mRNA, the expression of CCK-BR mRNA peaked at 2 h and kept a high level at 6 h, but it did not change at the first 0.5 h and was stable at a high level at 12 h. CONCLUSION: The above results indicate that endogenous and exogenous sCCK-8 may significantly improve cardiac function and intractable hypotension of ES rats, which was likely related to high expression of CCK-A/BR in myocardium induced by LPS.

Animals↗
PubMed2002

Effect of cholecystokinin octapeptide on tumor necrosis factor alpha transcription and nuclear factor-kappaB activity induced by lipopolysaccharide in rat pulmonary interstitial macrophages.

AIM: To elucidate the anti-inflammatory mechanism of an intestinal neuropeptide, sulfated cholecystokinin octapeptide (sCCK-8), the effects of sCCK-8 on lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNF-alpha) mRNA expression and NF-kappaB activity in pulmonary interstitial macrophages (PIMs) were studied. METHODS: PIMs from rat were stimulated with LPS (1 mg.L(-1)) in the presence or absence of sCCK-8 (10(-8)-10(-6)mol.L(-1)) or/and CCK receptor antagonist proglumide (2 mg.L(-1)). The expression of TNF-alpha mRNA was assayed by reverse transcription polymerase chain reaction (RT-PCR) at 3h of the stimulation, and nuclear factor-kappaB (NF-kappaB) binding activity was analyzed by electrophoretic mobility shift assay (EMSA) at 1 h of stimulation. The IkappaBalpha protein level in the cytoplasma at 30 min of the stimulation was detected by Western blot. RESULTS: sCCK-8, at concentrations from 10(-8) mol.L(-1) to 10(-6) mol.L(-1) obviously inhibited LPS-induced TNF-alpha mRNA expression and NF-kappaB binding activity in a dose-dependent manner, P<0.05, P<0.01. Stimulation PIMs with LPS resulted in a reduction of IkappaBalpha protein level, P<0.01, which was elevated by sCCK-8, P<0.05. The effects of sCCK-8 on NF-kappaB activity and IkappaB protein level were attenuated by CCK receptor antagonist proglumide, P<0.01. CONCLUSION: sCCK-8 inhibits LPS-induced TNF-alpha mRNA expression by regulating NF-kappaB activity in rat PIMs, which is mediated through CCK receptors and inhibiting IkappaB-alpha degradation. This represents one of the anti-inflammatory mechanisms of sCCK-8.

Animals↗
PubMed2002

Cholecystokinin octapeptide inhibits the in vitro expression of CD14 in rat pulmonary interstitial macrophages induced by lipopolysaccharide.

OBJECTIVE: To study the effect of cholecystokinin octapeptide (CCK-8) on lipopolysaccharide (LPS)-stimulated pulmonary interstitial macrophages (PIM) in vitro. METHODS: PIM were isolated and cultured in the presence or absence of LPS, CCK-8, proglumide (the antagonist of CCK receptors) and vehicle. The expression of membrane CD14 (mCD14) protein was assayed by flow cytometry and soluble CD14 (sCD14) in the supernatant was analyzed semi-quantitatively by Western blot. TNF-alpha in the supernatant was detected with ELISA. RESULTS: CCK-8, at concentrations of 10(-7) mol/L and 10(-6) mol/L, significantly inhibited the expression of mCD14. Release of sCD14 and TNF-alpha in the supernatant was up-regulated by LPS (1 microg/ml) but reduced by CCK-8. The effect of CCK-8 was inhibited by proglumide. CONCLUSION: CCK-8 negatively modulated several functions of LPS-stimulated PIM through CCK receptors. This may be one of the mechanisms for CCK-8 to alleviate inflammation in lung tissue during endotoxemia.

Animals↗
PubMed2002

[Effect of external gastrin on apoptosis and expression of bcl-2 gene in gastric cancer cells].

BACKGROUND & OBJECTIVE: It has been reported that external gastrin could facilitate the growth of the cells of gastrointestinal carcinomas. However, the modifying effect of gastrin on apoptosis of the gastric carcinoma has not been well appreciated. This study was designed to investigate the modifying effect of gastrin on apoptosis of the stomach cancer cell. METHODS: Flow cytometric analysis (FCM) and immunohistochemical dyeing are used to measure the rates of apoptosis and expression of bcl-2 gene in MKN45 cell line treated with gastrin and its receptor antagonist. RESULTS: Forty-eight hours later, the percentage of apoptosis cell in gastrin group was 1.39 +/- 0.54%, lower than that in control group (8.58 +/- 0.67%) (P < 0.01), but the expression rate of bcl-2 in gastrin treatment group was 22.3 +/- 5.3% higher than that in control group (P < 0.01). These effects were vanished after combined treatment with proglumide. CONCLUSIONS: External gastrin may restrain the apoptosis of MKN45 cell by inducing the expression of bcl-2 gene, and proglumide can block these effects of gastrin.

Apoptosis↗
PubMed2003

[Effects of cholecystokinin-octapeptide on the tension of pulmonary artery in rabbits with endotoxic shock].

For investigation of the regulatory mechanism of cholecystokinin-octapeptide (CCK-8) on pulmonary circulation in rabbits with endotoxic shock (ES) induced by lipopolysaccharides (LPS), mean arterial pressure (MAP) and pulmonary arterial pressure (PAP) were evaluated for 5 h in five groups of rabbits: group of LPS (8 mg/kg, i.v.)-induced ES, group of CCK-8 pretreatment (15 microg/kg, i.v.) 15 min before LPS administration (8 mg/kg, i.v.), group of proglumide pretreatment (1 mg/kg, i.v.) 15 min before LPS administration (8 mg/kg, i.v.), group of CCK (15 microg/kg, i.v.) only, and normal saline (control) group. The pulmonary arterial tension was measured with isolated vascular ring technique. The results showed that LPS-induced pulmonary arterial hypertension was abolished by CCK-8. In contrast, proglumide, a nonspecific antagonist of CCK-8 receptor, potentiated the deleterious effect of LPS. The contractile response of isolated pulmonary artery to alpha-adrenoceptor agonist phenylephrine (PE) was enhanced and the relaxation response to acetylcholine (ACh) was depressed significantly after LPS was injected, but the effect could be reversed by CCK-8. These results suggest that pulmonary circulation is improved by CCK-8 in ES, and the regulatory effects of CCK-8 may be brought about by modulating the pulmonary arterial tension.

Animals↗
PubMed1991

[Cholecystokinin-octapeptide antagonizes the central depressive effect of opioid peptides in rats].

Cholecystokinin-octapeptide (CCK-8) has been shown to antagonize the analgesia produced by opioid peptides. The present study was performed to evaluate its effect on cardiovascular regulatory functions of opioids. Both CCK-8 and opioid peptides were injected intrathecally (ith) in pentobarbital anaesthetized rats. The depressive effects induced by the mu agonist PL017 (5 micrograms), delta agonist DADLE (25 micrograms) and kappa agonist 66A-078 (1 microgram) were antagonized by CCK-8 within a dosage of 10 micrograms in a dose dependent manner. CCK-8 can also partly antagonize the bradycardiac effects induced by PL017, DADLE and 66A-078. The antagonistic effect of CCK-8 on DADLE in MAP could be reversed by pretreatment with CCK receptor antagonist proglumide (100 micrograms). No significant changes in MAP were found following ith administration of CCK-8 0.5-10 micrograms and proglumide 100 micrograms, but a large dose (50 micrograms) of CCK-8 lowered MAP dramatically. The results suggest that within a certain range of dose CCK-8 in spinal cord may play an antagonistic role against opioid effects in the regulation of cardiovascular function and this effect of CCK-8 seems to be mediated by CCK receptor. These results support the hypothesis that CCK-8 may act as an anti-opioid substance in the CNS of the rat.

Animals↗
PubMed1985

Involvement of histamine release in the mechanism of cysteamine-induced gastric acid hypersecretion.

To elucidate the mechanism of gastric hypersecretion induced by cysteamine, the effects of atropine, cimetidine, proglumide, cromolyn sodium and tranilast on the cysteamine response were studied in rats. Under urethane anesthesia, rat stomachs were perfused with 4 ml of physiological saline (pH 6.0) every 15 min. Acid secretion was progressively increased by cysteamine HCl (300 mg/kg, s.c.) for the duration of the experiment (6 hr). This effect was completely blocked by cimetidine and partially blocked by proglumide and atropine. Cromolyn sodium and tranilast, inhibitors of histamine release, also blocked cysteamine-induced acid hypersecretion. However, histamine-induced acid secretion was not affected by cromolyn sodium. It is concluded that the acid hypersecretion induced by cysteamine is mediated in part by histamine release.

Animals↗
PubMed1989

Cholecystokinin, but not gastrin, induces gamma-aminobutyric acid release from myenteric neurons of the guinea pig ileum.

Effects of cholecystokinin (CCK) and gastrin on the release of acetylcholine (ACh) and gamma-aminobutyric acid (GABA) were examined in the longitudinal muscle with myenteric plexus (LM-MP) preparations of the guinea pig small intestine. CCK and gastrin induced the Ca++-dependent and tetrodotoxin-sensitive release of [3H]ACh from the LM-MP preparations preloaded with [3H]choline. Proglumide, but not scopolamine, hexamethonium and [D-Pro2,D-Trp7,9]substance P inhibited the release of [3H]ACh induced by CCK and gastrin. The desensitization to CCK and gastrin was observed with a 30-min exposure of the preparation to CCK and gastrin, respectively, and the cross-desensitization to peptides was not observed, thereby indicating that these peptides induce the release of ACh mainly via respective receptors. Bicuculline which inhibited completely the release of [3H]ACh induced by GABA inhibited the release of [3H]ACh induced by CCK but not by gastrin by 42.3 +/- 4.22%. CCK, but not gastrin, produced the Ca++-dependent and tetrodotoxin-sensitive release of endogenous GABA and [3H]GABA from LM-MP preparations preloaded with [3H]GABA. The release of [3H]GABA induced by CCK was antagonized by proglumide, but not by scopolamine, hexamethonium and [D-Pro2,D-Trp7,9]substance P. These results provide evidence that the GABAergic neuron is stimulated by CCK, but not by gastrin and stimulates the cholinergic neuron.

Acetylcholine↗
PubMed1988

[Species differences in the behavioral effects of cerulein--an agonist of the receptors of the octapeptide cholecystokinin--in white mice and rats].

It has been shown in the behavioural experiments that combined pretreatment with haloperidol (0.25 mg/kg) and caerulein (40 micrograms/kg), and to a lesser extent pretreatment with caerulein alone caused long-term reversal of amphetamine (2 mg/kg) induced hyperexcitability in rats. Administration of proglumide (50 mg/kg), an antagonist of CCK-8 receptors, did not reverse long-term antiamphetamine effect of caerulein. In mice pretreatment with caerulein (50 and 100 micrograms/kg) alone or in combination with haloperidol (0.25 mg/kg) caused hypersensitivity to the behavioural effect of amphetamine (3 mg/kg). Intraventricular (I ng), but not systemic (100-500 micrograms/kg) administration of caerulein selectively antagonized seizures in mice induced by intraventricular administration of quinolinic acid (5 micrograms) and N-methyl-D-aspartate (0.2 microgram). Pretreatment with proglumide (50 mg/kg) reversed the anticonvulsive effect of caerulein in mice. In rats, caerulein failed to affect the seizures caused by intraventricular administration of quinolinic acid. The results of the present study demonstrate the existence of obvious interspecies differences in the behavioural effects of caerulein, the agonist of CCK-8 receptors, in mice and rats.

Amphetamine↗
PubMed1996

Involvement of spinal cholecystokininB receptors in mediating neurotensin hyperalgesia from the medullary nucleus raphe magnus in the rat.

Neurotensin microinjection into the medullary nucleus raphe magnus (RMg) has been shown to both inhibit and facilitate the spinal nociceptive tail-flick reflex in a dose-dependent manner. Our study was designed to determine a potential involvement of spinal cholecystokinin octapeptide (CCK) in mediating neurotensin hyperalgesia from the RMg. Microinjection of neurotensin (50 ng) into the RMg of awake rats produced a facilitation of the tail-flick reflex that was completely inhibited by intrathecal (i.t.) administration of the nonselective CCK receptor antagonist proglumide (100 ng). Conversely, injection of a greater dose of neurotensin (5 micrograms) into the RMg produced an inhibition of the tail-flick reflex that was enhanced by i.t. proglumide. Intrathecal administration of the selective CCKB receptor antagonist L-365260 dose-dependently inhibited neurotensin hyperalgesia from the RMg (ID50 = 0.42 ng) at doses approximately 1000-fold less than that observed with the selective CCKA receptor antagonist devazepide (ID50 = 646 ng). Injection of CCK alone i.t. produced a biphasic response on the tail-flick reflex as lesser doses (0.1-0.3 ng) inhibited the reflex although greater doses (30-100 ng) facilitated it. Similar to supraspinal neurotensin hyperalgesia, the hyperalgesia observed with i.t. CCK (30 ng) was inhibited by i.t. L-365260 (ID50 = 0.59 ng) at doses approximately 1000-fold less than that observed with i.t. devazepide (ID50 = 630 ng). These data indicate that spinal CCK can both inhibit and facilitate spinal nociceptive responses. The facilitation of nociception observed with spinal CCK appears to involve CCKB receptors, which is consistent with the data in our study suggesting that spinal CCKB receptors mediate neurotensin hyperalgesia from the RMg via descending neuronal projections.

Animals↗
PubMed1985

Residual inhibition of epidermal growth factor binding by pancreatic secretagogues and phorbol ester in rat pancreas.

Cholecystokinin-octapeptide (CCK8) inhibits 125I-labeled epidermal growth factor (EGF) cell-associated radioactivity in pancreatic acini, ostensibly as a result of its ability to mobilize cellular Ca2+. The phorbol ester tetradecanoyl phorbol acetate (TPA), a compound that activates protein kinase C, mimics the inhibitory action of CCK8. In the present study we examined the relationship between occupancy of the cholecystokinin (CCK) receptor, the subsequent inhibition of EGF binding, and the potential role of C-kinase activation in mediating this inhibition. Proglumide and dibutyryl cyclic GMP (dbGMP), two distinct competitive antagonists of CCK8, reversed the inhibitory actions of CCK8. Analysis of steady-state saturation kinetics of 125I-EGF binding indicated that CCK8 decreased the apparent affinity of the EGF receptor, mainly as a result of a marked decrease in the amount of internalized ligand. TPA also inhibited 125I-EGF internalization. Removal of CCK8 and TPA from incubation medium did not abolish their inhibitory actions. Carbachol, but not bombesin, exerted a similar residual inhibitory effect. It is suggested that in addition to acting via Ca2+, certain pancreatic secretagogues may also act through C-kinase to regulate EGF binding.

Animals↗
PubMedDate not supplied

Anxiogenic-like action of caerulein, a CCK-8 receptor agonist, in the mouse: influence of acute and subchronic diazepam treatment.

Effects of caerulein, a cholecystokinin octapeptide (CCK-8) receptor agonist, on exploratory activity of mice were investigated. Exploratory and locomotor activity of animals were measured using elevated plus-maze and open field tests. The systemic administration of caerulein at non-sedative doses (100 ng/kg-1 micrograms/kg i.p.) resulted in a significant decrease in the exploratory activity of mice. This effect was completely blocked by proglumide, a CCK-8 receptor. Acute treatment with low doses (0.1-0.75 mg/kg i.p.) of diazepam did not attenuate the anxiogenic-like effect of caerulein, but at more high doses of diazepam the coadministration depressed locomotor activity in mice. After subchronic diazepam treatment (2.5 mg/kg once a day, 10 days, i.p.) tolerance was developed toward the sedative effect of diazepam, and 72 h after withdrawal of the drug the animals showed increased anxiety in the plus-maze test. 30 min after the last injection procedure the anxiogenic-like effect of caerulein (500 ng/kg i.p.) on exploration was absent in both diazepam or vehicle groups. However, 72 h after the last pretreatment injection caerulein (500 ng/kg i.p.) reduced significantly the exploratory activity in control group, whereas it was inactive after diazepam withdrawal. The results obtained in this study support the hypothesis that endogenous CCK-8 an CCK-8 receptors are involved in the neurochemistry of anxiety and the anxiolytic action of benzodiazepine tranquillizers.

Animals↗