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PubMed2006

CCK1 antagonists: are they ready for clinical use?

Cholecystokinin (CCK) is a peptide hormone which is found both in the gastrointestinal tract throughout the human small intestine and nerves in the myenteric plexus of the enteric nervous system and in the central nervous system. This dual location constitutes the anatomical basis for this in functions as a hormone and a neurotransmitter implicated in the regulation of both systems. CCK regulates not only motor functions in the gastrointestinal tract like lower oesophageal sphincter relaxation, gastric secretion and emptying, gall bladder contractility and bile secretion into the duodenum, intestinal and colonic motility, but also sensory functions and plays a role in the regulation of food intake. These effects are mediated through selective receptors CCK1 and CCK2. Over the last few years, research has focused on understanding the role of CCK, its receptors with antagonists at the biological, pharmacological, clinical and therapeutic level. As far as the CCK1 antagonists is concerned, important inroads have been made in the potential role of these antagonists in the treatment of GERD, IBS and pancreatitis. They have also shown encouraging results in sphincter of Oddi dysfunction and some gastrointestinal cancers. This review focuses on the recent ad vances of the biological role of CCK and their CCK1 antagonists: their current basic and clinical status in gastroenterology, with particular emphasis on the potential therapeutic role of the CCK1 antagonists and future research directions.

Cholecystokinin↗
PubMed1989

Effect of a new CCK-receptor antagonist, CR 1409, on pancreatic growth induced by caerulein, CCK-8, bombesin and gastrin-releasing peptide in the rat.

The effect of a peripheral cholecystokinin (CCK)-receptor antagonist, CR 1409, on pancreatic growth has been studied in the rat. 1.8 nmol/kg CCK-8 or caerulein and 3.6 nmol/kg bombesin or gastrin-releasing peptide (GRP) administered subcutaneously 3 times daily for 4 successive days increased pancreatic weight and its content in protein, enzymes and RNA but not in DNA, suggesting cellular hypertrophy. CR 1409 (10 mg/kg) administered intragastrically 30 min prior to peptides prevented pancreatic growth due to CCK-8 or caerulein but not that induced by bombesin and GRP. It is concluded that bombesin and GRP act on the exocrine pancreas directly rather than through the release of CCK.

Animals↗
PubMed1990

Cholecystokinin in the inhibition of gastric secretion and gastric emptying in humans.

Cholecystokinin (CCK) is known to inhibit gastric acid secretion and gastric emptying but its physiological role in the inhibition of gastric functions is not settled. In this study performed on 16 young male subjects, gastric acid secretion and emptying rate were determined after intragastric administration of 8% peptone meal alone or in combination with intravenous infusion of graded doses of CCK-8 (5-80 pmol/kg.h) or with addition of vegetable oil to meal without or with pretreatment with loxiglumide, a specific CCK antagonist. CCK-8 infusion at lower dose (5 pmol/kg.h) was ineffective but at higher doses (20-80 pmol/kg.h) it resulted in a significant reduction in acid output by 39 and 43% and a decrease in gastric emptying from 54% to 40 and 22%, respectively. Pretreatment with loxiglumide abolished almost completely the inhibition of both gastric acid and gastric emptying by CCK-8. Fat added to peptone meal reduced gastric acid secretion by 42-65% and decreased gastric emptying to 24-32%. The pretreatment with loxiglumide tended to reduce fat-induced inhibition of gastric acid secretion and gastric emptying but the difference in the inhibition of gastric functions between the tests without and with loxiglumide was not significant. This study provides evidence that exogenous CCK administered at pharmacological doses is a potent inhibitor of gastric acid secretion and gastric emptying and probably acts via specific CCK receptors. In contrast, fat induces inhibition of gastric acid secretion and gastric emptying that cannot be fully attributed to hormonally acting CCK.

Adult↗
PubMed1990

Effects of long-term CCK stimulation and CCK blockade on pancreatic and intestinal growth, morphology, and function.

This study evaluated the effects of long-term cholecystokinin (CCK) stimulation and blockade on pancreatic and intestinal growth, function, and morphology. CCK release was induced by feeding of the protease inhibitor camostate and CCK blockade by feeding of the CCK antagonist CR 1409. Four groups of NMRI-mice received the following diets for 9 months (each group consisting of 36 mice): (1) chow (control); (2) chow + 100 mg/kg/day camostate; (3) chow + 50 mg/kg/day CR 1409; (4) chow + 100 mg/kg/day camostate + 50 mg/kg/day CR 1409. Long-term feeding of camostate greatly increased pancreatic weight by induction of marked hypertrophy (increase in protein content) and moderate hyperplasia (increase in DNA content). Camostate feeding also increased secretory capacity of the exocrine pancreas. Despite camostate-induced growth neither hyperplastic nor neoplastic nodules developed. The CCK-antagonist CR 1409 markedly inhibited the effects of camostate which are therefore mainly mediated by CCK. Neither long-term CCK stimulation nor CCK blockade altered morphology or composition of duodenal mucosa. Feeding of CR 1409 alone (i.e., without camostate) slightly but significantly decreased pancreatic content of protein and secretory capacity of enzymes when compared to the chow-fed control; pancreatic weight and DNA content remained unchanged after long-term administration of CR 1409. Thus, long-term, continuous and effective blockade of the CCK-receptor only slightly inhibited pancreatic growth and secretory capacity. CCK is, therefore, not an essential growth factor for the pancreas, although increases of endogenous CCK stimulate pancreatic growth and secretory capacity.

Animals↗
PubMed1990

Cholecystokinin receptor antagonist loxiglumide: influence on bilio-pancreatic secretion and gastrointestinal hormones in man.

We characterized the effect of the specific cholecystokinin (CCK) receptor antagonist loxiglumide (CR 1505) on gallbladder contraction, pancreatic enzyme output and plasma CCK concentrations determined by radioimmunoassay and bioassay. Gallbladder emptying and bilirubin output in response to the intraduodenal administration of a mixed liquid meal were completely inhibited by an intravenous infusion of loxiglumide (10 mg/kg/h). In contrast, meal-stimulated pancreatic enzyme secretion was diminished by only 30-40%. CCK concentrations in response to the test meal were 3-fold higher during infusion of loxiglumide, as determined by radioimmunoassay. In the absence of the antagonist, the bioassay measured CCK plasma levels identical to those determined by radioimmunoassay. In the presence of loxiglumide, CCK-like bioactivity was not detectable, indicating that the plasma concentrations of the CCK receptor antagonist were sufficient to abolish all circulating CCK-like bioactivity. We conclude that fasting volume and meal-induced contraction of the gallbladder are controlled by CCK. Postprandial pancreatic enzyme secretion, however, is mainly mediated by non-CCK-dependent mechanisms. Plasma CCK-like immunoreactivity is increased by loxiglumide, whereas plasma CCK-like bioactivity is zero in the presence of an CCK-receptor antagonist.

Adult↗
PubMed1991

CCK receptor antagonist loxiglumide alters uptake of CCK in perfused liver and pancreatic acini of the rat.

The aim of the present study was to analyze the effect of the specific cholecystokinin (CCK) receptor antagonist loxiglumide on hepatic and pancreatic processing of CCK-8 and the CCK analogue cerulein. Rat liver perfusion was performed in a non-recirculating system. CCK concentrations were measured by radioimmunoassay in perfusates from the inflow cannula (portal vein) and the outflow cannula (hepatic vein). In rat pancreatic acini, the effect of loxiglumide on internalization and surface-binding of radiolabelled CCK-8 was determined. Cerulein (20 nM, 2 nM) was extracted in a single pass through the liver by 29.7 and 25.4%, respectively. The hepatic uptake of CCK-8 (50 pM, 2 nM) was more than 90 and 89.9%, respectively. Loxiglumide drastically inhibited hepatic extraction of both peptides and reduced internalization of 125I-CCK-8 in pancreatic acini dose dependently by 39-93%. These results demonstrate that the potent CCK receptor antagonist loxiglumide significantly decreased CCK uptake by the liver and pancreas.

Animals↗
PubMed1992

Role of endogenously released cholecystokinin in determining postprandial insulin levels in man: effects of loxiglumide, a specific cholecystokinin receptor antagonist.

To estimate the contribution of postprandial cholecystokinin (CCK) responses to circulating insulin concentrations and insulin secretion, a specific CCK receptor antagonist (loxiglumide; 10 mg/kg body weight/h) or saline were infused intravenously in normal volunteers, beginning 90 min before insulin secretion was stimulated on separate occasions by the intraduodenal administrations of glucose, glucose and protein, and glucose plus protein with the admixture of pancreatin. The release of CCK (radioimmunoassay) was stimulated by the protein component of the nutrients from basal 2.4 +/- 0.4 to 8.0 +/- 1.2 pmol/l. CCK plasma levels were significantly higher with loxiglumide (p < 0.05). Glucose-dependent insulinotropic polypeptide (GIP) was also released by all nutrient mixtures. Loxiglumide significantly inhibited the amount of bilirubin and pancreatic enzymes recovered from duodenal aspirates. In contrast, in none of the experiments, C-peptide increments and hence insulin secretion rates were altered by loxiglumide. With glucose and protein as intraduodenal stimulus (no pancreatin added), the plasma amino acids rose significantly less (by approximately 50% of the control experiment) and the increment in insulin (but not C-peptide) concentrations was significantly reduced by loxiglumide. This is most likely explained by a change in insulin metabolic clearance. This effect cannot be a primary action of CCK because there was no similar effect of loxiglumide with the same intraduodenal stimulus plus added pancreatin. Pancreatic enzymes reduced maldigestion secondary to loxiglumide effects on pancreatic exocrine secretion: The increment in circulating amino acid concentrations was similar with and without loxiglumide. In conclusion, CCK does not alter insulin secretion and, therefore, is not an incretin hormone in man. Blocking CCK actions on the exocrine pancreas by loxiglumide, however, can secondarily cause reductions in postprandial insulin profiles by altering insulin clearance. These changes are possibly related to reductions in circulating amino acid concentrations.

Adult↗
PubMed1994

Implication of cholecystokinin in pancreatic adaptation after biliopancreatic bypass in the rat.

Biliopancreatic bypass (BPB), a bariatric surgical procedure, leads to a malnutrition-induced general visceral atrophy except for the pancreas. This work investigates the implication of cholecystokinin (CCK) in the exocrine pancreatic adaptive process using a plasma CCK assay and the CCK receptor antagonist CR 1409. No significant reduction in weight and DNA content of the pancreas was noted 36 days after BPB, while a strong decrease in protein, enzymes and RNA contents indicating cellular hypotrophy became apparent. CR 1409 treatment strongly depressed pancreatic weight and its DNA content in BPB animals, suggesting an additional hypoplasia; however, the reduction in pancreatic enzyme content was not aggravated. BPB increased plasma CCK concentrations by 160%, unrelated to CR 1409 treatment. These results indicate that: (1) CCK is involved in the pancreatic adaptive response after BPB in rats, and (2) in the context of a protein malnutrition state, CCK dissociates its pancreatic growth and enzymatic effects, favouring the former.

Adaptation, Physiological↗
PubMed1994

Regulation of pancreatic polypeptide release is mediated through M3 muscarinic receptors.

The purpose of this study was to determine the regulation of pancreatic polypeptide (PP) release by using pirenzepine (a specific M1 muscarinic receptor antagonist), 4-diphenylacetoxy-N-methylpiperidine methobromide (4-DAMP, a specific M3 muscarinic receptor antagonist), atropine (a nonspecific muscarinic receptor antagonist), and loxiglumide (cholecystokinin, CCK, receptor antagonist) in dogs. In conscious dogs with chronic gastric and duodenal fistulas, release of PP and exocrine pancreatic secretion were stimulated by constant intravenous infusion of CCK-8 (200 ng/kg/h). Graded doses of pirenzepine (0.18-4.7 mmol/kg/h), 4-DAMP (6.7-180 nmol/kg/h), or atropine (0.89-24 nmol/kg/h) dose-dependently reduced plasma PP responses to CCK-8 without influence on exocrine pancreatic secretion. ID50 calculated from these results were 492 +/- 150 nmol/kg/h for pirenzepine, 10.7 +/- 1.8 nmol/kg/h for 4-DAMP and 19.4 +/- 5.2 nmol/kg/h for atropine. A similar sequence in the inhibitory potency was observed in 2-deoxy-D-glucose (2-DG, 100 mg/kg)-stimulated PP release, exocrine pancreatic, and gastric secretions. On the other hand, loxiglumide, a CCK receptor antagonist, did not influence PP release stimulated by 2-DG. These findings suggest that both CCK- and 2-DG-stimulated PP releases are mainly under cholinergic nerve control mediated by M3 muscarinic receptor in dogs.

Animals↗
PubMed1990

Effects of a cholecystokinin receptor antagonist on intestinal phase of pancreatic and biliary responses in man.

The present study was designed (a) to characterize the activity of loxiglumide as a peripheral cholecystokinin (CCK) antagonist in healthy human subjects, and (b) to determine whether CCK is a physiologic regulator of the intestinal phase of meal-stimulated exocrine pancreatic and biliary secretions in man. Intravenous loxiglumide (22 mumol/kg per h) was highly potent in antagonizing CCK8-induced pancreatic enzyme and bile acid secretion as well as pancreatic polypeptide release. The potency and selectivity of loxiglumide as an antagonist of CCK provides the tool for evaluating the role of CCK as a physiological mediator of meal-induced pancreatic and biliary responses in humans. Infusion of a liquid test meal into the duodenum evoked an immediate response of pancreatic enzyme and bilirubin outputs, respectively. Intravenous loxiglumide significantly inhibited the meal-induced pancreatic amylase output by 63% (P less than 0.05), lipase output by 43% (P less than 0.05), and bilirubin output by 59% (P less than 0.05). These data suggest that CCK is a physiological mediator of the intestinal phase of meal-stimulated pancreatic and biliary responses.

Adult↗
PubMed1997

Effects of a specific CCK-A antagonist, Loxiglumide, on postprandial mood and sleepiness.

Previous studies have demonstrated that feelings of sleepiness increase after ingestion of a fat-rich meal. The aim of the study was to test the hypothesis that postprandial sleepiness is mediated by cholecystokinin (CCK) acting on CCK-A receptors. A double-blind crossover study was conducted. Twelve male volunteers ate a high-fat morning meal [54% energy fat, 41% energy carbohydrate (CHO)]. On one day they received an i.v. infusion of Loxiglumide, a CCK-A receptor antagonist (30 mg/kg/h for 10 min then 10 mg/kg/h for 3 h 10 min). On another day the protocol was repeated except a saline placebo infusion was given at similar rates as the Loxiglumide, starting 20 min before the meal. Subjects' mood and sleepiness were monitored throughout using questionnaires and performance tasks. The results indicate that ratings of vigour were significantly lower during the Loxiglumide infusion than during the saline infusion, [F(1,10) = 6.65; p = 0.027]. Subjects who were infused with Loxiglumide on their first test day felt significantly (p < 0.05) more fatigued, sleepy and tense and less vigorous, less efficient and had lower energetic arousal during the Loxiglumide infusion than during the saline infusion. In conclusion, the results suggest that the postprandial decline in feelings of alertness after a fat-rich meal is not mediated solely by CCK acting through CCK-A receptors.

Adult↗
PubMed1991

Effect of a cholecystokinin antagonist on meal-stimulated insulin and pancreatic polypeptide release in humans.

A cholecystokinin (CCK) receptor antagonist, loxiglumide, was used to investigate the potential regulating role of CCK in the entero-insular axis in humans. Ingestion of a mixed liquid meal stimulated plasma CCK, insulin, and pancreatic polypeptide (PP) release in the control experiment. With iv loxiglumide (22 mumol/kg.h), mean plasma insulin and glucose levels did not differ between placebo and loxiglumide treatment. The area under the plasma concentration for PP was reduced to 6,060 +/- 1,706 (P less than 0.05) compared to that during placebo treatment (12,266 +/- 4,748). Administration of loxiglumide failed to change insulin secretion in response to perfusion of the same meal or perfusion of a 10-amino acid solution into the duodenum. However, PP secretion in response to the intraduodenal meal or amino acid mixture was abolished after loxiglumide (P less than 0.05). Intravenous administration of the 10-amino acid mixture stimulated insulin from a mean basal level of 7 +/- 3 microU/mL to a peak level of 16 +/- 4 microU/mL. Infusion of a CCK octapeptide (CCK-8) at 8.6 pmol/kg.h, which produced a plasma concentration of 3.3 pmol/L, which is within the postprandial range, augmented amino acid-stimulated insulin and PP output (P less than 0.05). When CCK-8 was infused with loxiglumide, the insulin and PP responses were similar to the values found with loxiglumide alone. We conclude that CCK receptor blockade with iv loxiglumide does not affect postprandial insulin secretion. CCK is, therefore, not a major incretin. However, it is involved in the postprandial PP response, especially during the intestinal phase stimulation. These data suggest that CCK has a role in the human enteroinsular axis.

Adult↗
PubMed1993

Bombesin reduces food intake in lean man by a cholecystokinin-independent mechanism.

This double blind study was undertaken to determine whether infusion of bombesin (BBS) inhibits the intake of a carbohydrate-rich meal in nine lean healthy subjects and whether inhibition of food intake by BBS is mediated by cholecystokinin (CCK). During infusion of BBS, the amount of food eaten was decreased compared to that after saline infusion (482 +/- 74 vs. 602 +/- 68 g; P < 0.01). Subjective criteria of satiation were also significantly affected by BBS infusion (P < 0.05). Administration of the CCK receptor antagonist loxiglumide (CR1505) to six of the subjects did not prevent the decrease in food intake due to BBS (365 +/- 69 g) or the subjective criteria for satiety. Furthermore, the amount of food eaten during loxiglumide treatment alone (537 +/- 109 g) was not different from that during control saline infusion. In conclusion, infusion of BBS inhibits the intake of a carbohydrate-rich meal by a CCK-independent mechanism.

Adult↗
PubMed1995

Loxiglumide, L-364,718 and L-365,260 prevent the inhibition of spontaneous acetylcholine release from the frontal cerebral cortex of freely moving rat peripherally administered with cholecystokinin-8S.

We examined the effect of peripheral administration of cholecystokinin (CCK)-8S on spontaneous acetylcholine (ACh) release from the frontal cortex and its prevention by loxiglumide, L-364,718 and L-365,260 in freely moving rats using intracerebral microdialysis. Subcutaneously (s.c.) administered CCK-8S at 10 and 30 micrograms/kg significantly decreased the release of ACh. The inhibitory effect of 10 micrograms/kg (s.c.) CCK-8S was prevented by loxiglumide, a mixed type of CCK-A and -B-receptor antagonist, at 1 mg/kg (intraperitoneal) and 40 micrograms/rat (intracerebroventricular, i.c.v.); L-364,718, a CCK-A-receptor antagonist, at 125 and 250 ng/rat (i.c.v.); and L-365,260, a CCK-B-receptor antagonist at 250 ng/rat (i.c.v.). These results demonstrate that peripherally administered CCK-8S inhibits spontaneous ACh release from the frontal cortex through both central CCK-A (mainly) and -B receptors.

Acetylcholine↗
PubMed1997

Effect of T-0632, a cholecystokininA receptor antagonist, on experimental acute pancreatitis.

Effects of a new cholecystokinin (CCK)A-receptor antagonist, T-0632 [sodium (S)-1-(2-fluorophenyl)-2, 3-dihydro-3-[(3-isoquinolinylcarbonyl) amino]-6-methoxy-2-oxo-1H-indole-3-propanoate], on caerulein-induced and pancreatic duct ligation-induced pancreatitis models were studied and compared with the CCKA-receptor antagonist loxiglumide and the orally active protease inhibitor camostate, respectively. In rats, orally administered T-0632 potently prevented the caerulein-induced increases in pancreatic digestive enzymes in plasma and suppressed the histological changes in the pancreas. The estimated ED50 values of T-0632 and loxiglumide were 0.0092 and 8.9 mg/kg, respectively. In dogs, T-0632 (0.1, 1 mg/kg, i.d.) prevented the caerulein-induced increase in plasma amylase activity in a dose-dependent manner. Loxiglumide (100 mg/kg, i.d.) did not show any preventive effects. In pancreatic duct ligation (6 hr)-induced pancreatitis of the rat, T-0632 (0.001-0.1 mg/kg, p.o.) partially prevented both the increase in plasma amylase activity and the histological changes in the pancreas, whereas camostate (10, 100 mg/kg, p.o.) did not show any preventive effects. In pancreatic duct ligation (3 hr)-induced pancreatitis, caerulein injection (1 microgram/kg, s.c.) caused a further increase in plasma amylase activity, and T-0632 (0.01, 0.1 mg/kg, p.o.) dose-dependently decreased the aggravation by caerulein. We conclude that T-0632 showed preventive effects on all of these pancreatitis models by oral or intraduodenal administration. These results suggest that CCK plays an important role in progression and aggravation of acute pancreatitis, and T-0632 may have a therapeutic value in these disease states.

Acute Disease↗
PubMed1999

Supraspinal neurotensin-induced antianalgesia in mice is mediated by spinal cholecystokinin.

Intracerebral injection of neurotensin into specific brain loci in rats produces hyperalgesia due to the release of cholecystokinin (CCK) in the spinal cord. The present purpose was to show in another species that neurotensin can antagonize the antinociceptive action of morphine through the spinal CCK mechanism in mice. Neurotensin given intracerebroventricularly (i.c.v.) at doses higher than 100 ng produced antinociception in the tail flick test. However, at lower doses between 1 pg to 25 ng, neurotensin antagonized the antinociceptive action of morphine given intrathecally (i.t.), thus demonstrating the antianalgesic activity of neurotensin. The rightward shift in the morphine dose-response curve produced by i.c.v. neurotensin was eliminated by an i.t. pretreatment with CCK8 antibody (5 microl of antiserum solution diluted 1:1000). I.t. administration of lorglumide, a CCK(A)-receptor antagonist (10-1000 ng), and PD135,158, a CCK(B)-receptor antagonist (250-500 ng), also eliminated the antianalgesic action of neurotensin. Thus, the mechanism of the antianalgesic action of neurotensin given i.c.v. involved spinal CCK. This mode of action is similar to that for the antianalgesic action of supraspinal pentobarbital which also involves spinal CCK.

Analgesics, Opioid↗
PubMedDate not supplied

Puerperal blockade of cholecystokinin (CCK1) receptors disrupts maternal behavior in lactating rats.

Blockade of cholecystokinin (CCK) receptors potentiates the morphine-induced disruption of maternal behavior. The present study was undertaken to determine whether treatment with lorglumide, a CCK1 antagonist during late pregnancy and early lactation can influence the maternal behavior during lactation. A possible influence of this treatment on general activity was also assessed. Twenty-seven female Wistar rats were pretreated with lorglumide (1.0mg/kg/day; sc) or saline for seven days, starting on the 17th d of pregnancy. After the withdrawal of this treatment, animals were acutely challenged with saline on day 5 and with morphine sulfate (3.0mg/kg; sc) on days 6,10, and 17 of lactation. Groups were pretreated with saline and challenged with saline (group SS) and morphine (group SM), pretreated with lorglumide and challenged with saline (group LS) and morphine (group LM). Animals were also tested for general activity on days 25 and 33 postpartum after an acute challenge with saline and morphine, respectively. Maternal behavior testing began 30 min after the acute injections at which time pups were placed throughout each mother's cage. Latencies for pup retrieval, grouping, crouching and for full maternal behavior responses were scored. Lorglumide pretreatment inhibited maternal behavior of LS vs SS group and potentiated the morphine-induced disruption of this behavior in all days of test (LM vs SM group). No significant differences were found in general activity on days 25 and 33 postpartum. These data suggest that blockade of CCK1 receptors during puerperal period has long-term implications for maternal behavior.

Animals↗
PubMed2005

Proopiomelanocortin neurons in nucleus tractus solitarius are activated by visceral afferents: regulation by cholecystokinin and opioids.

The nucleus tractus solitarius (NTS) receives dense terminations from cranial visceral afferents, including those from the gastrointestinal (GI) system. Although the NTS integrates peripheral satiety signals and relays this signal to central feeding centers, little is known about which NTS neurons are involved or what mechanisms are responsible. Proopiomelanocortin (POMC) neurons are good candidates for GI integration, because disruption of the POMC gene leads to severe obesity and hyperphagia. Here, we used POMC-enhanced green fluorescent protein (EGFP) transgenic mice to identify NTS POMC neurons. Intraperitoneal administration of cholecystokinin (CCK) induced c-fos gene expression in NTS POMC-EGFP neurons, suggesting that they are activated by afferents stimulated by the satiety hormone. We tested the synaptic relationship of these neurons to visceral afferents and their modulation by CCK and opioids using patch recordings in horizontal brain slices. Electrical activation of the solitary tract (ST) evoked EPSCs in NTS POMC-EGFP neurons. The invariant latencies, low failure rates, and substantial paired-pulse depression of the ST-evoked EPSCs indicate that NTS POMC-EGFP neurons are second-order neurons directly contacted by afferent terminals. The EPSCs were blocked by the glutamate antagonist 2,3-dihydroxy-6-nitro-7-sulfonyl-benzo[f]quinoxaline. CCK increased the amplitude of the ST-stimulated EPSCs and the frequency of miniature EPSCs, effects attenuated by the CCK1 receptor antagonist lorglumide. In contrast, the orexigenic opioid agonists [D-Ala(2), N-Me-Phe(4), Gly-ol(5)]-enkephalin and met-enkephalin inhibited both ST-stimulated EPSCs and the frequency of miniature EPSCs. These findings identify a potential satiety pathway in which visceral afferents directly activate NTS POMC-EGFP neurons with excitatory inputs that are appropriately modulated by appetite regulators.

Animals↗