CCK Infusion Research Articles

The Role of Cholecystectomy in Hyperkinetic Gallbladder: A Retrospective Cohort Study in a Rural Hospital.

Background Biliary dyskinesia is a functional gallbladder disorder in which there is an absence of a structural or mechanical cause for biliary pain. A cholecystokinin-hepatobiliary iminodiacetic acid (CCK-HIDA) scan is typically performed during workup, and cholecystectomy is the accepted treatment for low ejection fraction (EF) (less than 33%, as defined by the literature). However, few studies have examined the role of cholecystectomy in hyperkinetic gallbladder (EF ≥80%). The aim of our study was to examine symptom resolution following minimally invasive cholecystectomy in patients with hyperkinetic gallbladder. Methodology A retrospective chart review was conducted at Robert Packer Hospital in Sayre, PA. Patients who underwent minimally invasive cholecystectomy for biliary colic with EF ≥80% and who were without cholelithiasis on preoperative imaging or on final pathology were included in this study. The main outcome was symptom resolution at the postoperative visit. Data collected included age, gender, EF, body mass index, symptoms with CCK infusion, and pathology. Results A total of 48 patients were included. The mean age of patients was 41.2 years (standard deviation = 14.4), and the median age of patients was 42.2 years, with a range of 17-71 years. The majority of patients were female (83.3%). Overall, 58.3% of patients had replication of symptoms with CCK infusion. The mean gallbladder EF was 87.3%, with a median of 87.0 and a range of 80-98. In total, 33 (68.8%) patients had chronic cholecystitis on final pathology reports. There was a 95.9% symptom resolution rate among our patients two weeks postoperatively. Conclusions The overwhelming majority of patients experienced symptom resolution prior to their two-week postoperative visit following minimally invasive cholecystectomy for hyperkinetic gallbladder. These results strongly suggest a role of surgical management in patients with high EF.

Somatodendritic Release of Cholecystokinin Potentiates GABAergic Synapses Onto Ventral Tegmental Area Dopamine Cells

BackgroundNeuropeptides are contained in nearly every neuron in the central nervous system and can be released not only from nerve terminals but also from somatodendritic sites. Cholecystokinin (CCK), among the most abundant neuropeptides in the brain, is expressed in the majority of midbrain dopamine neurons. Despite this high expression, CCK function within the ventral tegmental area (VTA) is not well understood. MethodsWe confirmed CCK expression in VTA dopamine neurons through immunohistochemistry and in situ hybridization and detected optogenetically induced CCK release using an enzyme-linked immunosorbent assay. To investigate whether CCK modulates VTA circuit activity, we used whole-cell patch clamp recordings in mouse brain slices. We infused CCK locally in vivo and tested food intake and locomotion in fasted mice. We also used in vivo fiber photometry to measure Ca2+ transients in dopamine neurons during feeding. ResultsHere we report that VTA dopamine neurons release CCK from somatodendritic regions, where it triggers long-term potentiation of GABAergic (gamma-aminobutyric acidergic) synapses. The somatodendritic release occurs during trains of optogenetic stimuli or prolonged but modest depolarization and is dependent on synaptotagmin-7 and T-type Ca2+ channels. Depolarization-induced long-term potentiation is blocked by a CCK2 receptor antagonist and mimicked by exogenous CCK. Local infusion of CCK in vivo inhibits food consumption and decreases distance traveled in an open field test. Furthermore, intra-VTA–infused CCK reduced dopamine cell Ca2+ signals during food consumption after an overnight fast and was correlated with reduced food intake. ConclusionsOur experiments introduce somatodendritic neuropeptide release as a previously unknown feedback regulator of VTA dopamine cell excitability and dopamine-related behaviors.

Role of cholecystokinin in satiation: a systematic review and meta-analysis.

The aim of this review was to examine: (1) the ability of cholecystokinin (CCK) or analogues of CCK to influence satiation and changes in body weight generally and (2) the efficacy of CCK in influencing satiation and eating behaviour specifically at physiological levels of dosing. A systematic review of the literature was performed following the PRISMA 2020 guidelines in five electronic databases investigating the effect of exogenous CCK or analogues on satiation and body weight. A meta-analysis of studies that infused CCK and measured satiation via changes in food/energy intake was also conducted. A total of 1054 studies were found using the search terms which were reduced to fifteen studies suitable for inclusion. Of the twelve studies measuring the effect on the weight of food ingested or energy intake, eleven showed a decrease. An analogue of CCK which can be administered orally failed to produce any weight loss at 24 weeks. The meta-analysis found the effect of CCK on satiation dosed at physiological levels was significant with a standardised mean difference of 0·57 (95 % CI 0·30, 0·85, P < 0·0001). By comparison, CCK dosed at higher, pharmacological levels also had a significant effect with a standardised mean difference of 0·91 (95 % CI 0·46, 1·36, P < 0·0001). Eight of the ten studies in the meta-analysis combined CCK infusion with some means to facilitate stomach distension. The present review found evidence that at both physiological and pharmacological levels of dosing CCK has a significant effect on satiation but no evidence for weight loss over the long term.

Biliary hyperkinesia: an indication for cholecystectomy?

The main indications for laparoscopic cholecystectomy are stone-related diseases in adults. With a normal abdominal ultrasound (US), a hepatobiliary iminodiacetic acid (HIDA) scan with ejection fraction (EF) is recommended to evaluate gallbladder function. Biliary dyskinesia or low gallbladder EF (EF < 35%) is a recognized indication for cholecystectomy. Recent articles report long-term resolution of symptoms in children with high EFs on the HIDA scan. The purpose of this study is to evaluate the response of patients with biliary colic and hyperkinetic gallbladder to cholecystectomy. We suggest that laparoscopic cholecystectomy might be a considerable surgical option in a subset of the adult population whose workup for food-related biliary abdominal pain is negative except for the high-value EF on HIDA scan. Data were consecutively collected from all patients who underwent laparoscopic cholecystectomy between June 2012 and June 2019 at a single institution. Cases were identified using Current Procedural Terminology codes. Patients older than 17years of age with the negative US (no stone, no sludge, no gallbladder wall thickening) and EF greater than 80% on cholecystokinin (CCK)-HIDA scan were included in this study. All patients were seen at 2weeks and 10-16months after surgeries. Over 7years from June 2012 until June 2019, of 2116 patients who underwent laparoscopic cholecystectomy, 59 patients (2.78%) met study criteria. Postprandial abdominal pain was the most common symptom (43, 72.90%) followed by nausea/vomiting. Forty-seven patients (74.6%) had a reproduction of symptoms with CCK infusion. The average EF was 88.51%. Final pathology showed chronic cholecystitis in 41 (69.5%) patients, cholesterolosis in 13 (22%), polyp in 2 (3.4%). Thirty-six (61%) patients had complete resolution of symptoms, 9 (15%) patients had partial resolution, and 14 (24%) patients had no change. There was a complete resolution rate of 61% and an improvement rate of 76%. In patients with biliary symptoms, negative ultrasound, and elevated EF on HIDA scan (EF > 80%), laparoscopic cholecystectomy led to a significant rate of symptomatic relief. Interestingly, 94% also had unexpected pathologic findings. This disease process requires further analysis, but this could represent a new indication for laparoscopic cholecystectomy in the adult population.

Combined effects of cholecystokinin-8 and gastric distension on food intake in humans.

In a previous study (Kissileff HR, Carretta JC, Geliebter A, Pi-Sunyer FX. Am J Physiol Regul Integr Comp Physiol 285: R992-R998, 2003), when subthreshold gastric distension (300 ml) and a low dose of cholecystokinin octapeptide (CCK-8) (112 ng/min for 21 min) were concurrently administered to human participants, intake of a test meal was significantly reduced. However, the supra-additive interaction of CCK-8 and gastric distension was not significant. The purpose of the present study was to determine whether a significant interaction would be obtained when CCK-8 and gastric distension were each increased by 50% above levels used in the previous study. Twelve normal-weight, healthy participants were tested four times each with either CCK-8 (168 ng/min for 30 min) or saline infusion crossed with gastric distension (450 ml) or no distension. The combination of CCK-8 and gastric distension reduced food intake by a mean of 405 ± 86 g (SE) in comparison with the saline nondistension condition (P < 0.001), which is a 51% reduction. Although there were some differences in the protocols, the combined effect was double that seen in the previous study. Although the interactive effect was larger [118 ± 109 g (SE)] than it was previously [73 ± 86 (SE)], it was not significant (P = 0.29). There were also reports of a short-lived sick feeling after CCK-8, with and without distension, that was not observed in the previous study. Thus the combination of CCK-8 at 1.5 times threshold and gastric distension at 450 ml (increased from 300 ml) resulted in a combined effect to reduce food intake, which was also 1.5 times its previous value, and thus appears linear.

Cholecystokinin release triggered by NMDA receptors produces LTP and sound–sound associative memory

Memory is stored in neural networks via changes in synaptic strength mediated in part by NMDA receptor (NMDAR)-dependent long-term potentiation (LTP). Here we show that a cholecystokinin (CCK)-B receptor (CCKBR) antagonist blocks high-frequency stimulation-induced neocortical LTP, whereas local infusion of CCK induces LTP. CCK-/- mice lacked neocortical LTP and showed deficits in a cue-cue associative learning paradigm; and administration of CCK rescued associative learning deficits. High-frequency stimulation-induced neocortical LTP was completely blocked by either the NMDAR antagonist or the CCKBR antagonist, while application of either NMDA or CCK induced LTP after low-frequency stimulation. In the presence of CCK, LTP was still induced even after blockade of NMDARs. Local application of NMDA induced the release of CCK in the neocortex. These findings suggest that NMDARs control the release of CCK, which enables neocortical LTP and the formation of cue-cue associative memory.

Acquisition of analgesic properties by the cholecystokinin (CCK)/CCK2 receptor system within the amygdala in a persistent inflammatory pain condition

Pain is associated with negative emotions such as anxiety, but the underlying neurocircuitry and modulators of the association of pain and anxiety remain unclear. The neuropeptide cholecystokinin (CCK) has both pronociceptive and anxiogenic properties, so we explored the role of CCK in anxiety and nociception in the central amygdala (CeA), a key area in control of emotions and descending pain pathways. Local infusion of CCK into the CeA of control rats increased anxiety, as measured in the light-dark box test, but had no effect on mechanical sensitivity. By contrast, intra-CeA CCK infusion 4 days after Complete Freund's Adjuvant (CFA) injection into the hindpaw resulted in analgesia, but also in loss of its anxiogenic capacity. Inflammatory conditions induced changes in the CeA CCK signaling system with an increase of CCK immunoreactivity and a decrease in CCK1, but not CCK2, receptor mRNA. In CFA rats, patch-clamp experiments revealed that CCK infusion increased CeA neuron excitability. It also partially blocked the discharge of wide dynamic range neurons in the dorsal spinal cord. These effects of CCK on CeA and spinal neurons in CFA rats were mimicked by the specific CCK2 receptor agonist, gastrin. This analgesic effect was likely mediated by identified CeA neurons projecting to the periaqueductal gray matter that express CCK receptors. Together, our data demonstrate that intra-CeA CCK infusion activated a descending CCK2 receptor-dependent pathway that inhibited spinal neuron discharge. Thus, persistent pain induces a functional switch to a newly identified analgesic capacity of CCK in the amygdala, indicating central emotion-related circuit controls pain transmission in spinal cord.

Is hyperkinetic gallbladder an indication for cholecystectomy?

The (99m) technetium-labelled hepato imino diacetic acid (HIDA) scan is widely used to evaluate patients with biliary colic with a normal trans-abdominal ultrasound scan. Most studies recommend cholecystectomy for patients with biliary dyskinesia, defined by gallbladder ejection fraction (GBEF) of less than 35-40% on HIDA scan. There are no recommendations regarding management of hyperkinetic gallbladder defined by GBEF of greater than 80% on HIDA scan. The aim of our study was to evaluate the outcomes following cholecystectomy on patients with biliary colic associated with hyperkinetic gallbladder. We performed a retrospective chart review of all patients with biliary colic associated with hyperkinetic gallbladder that underwent cholecystectomy in our practice from July 2014 to February 2018. Data collection included age, gender, body mass index, preoperative symptoms, comorbidities, additional tests, ejection fraction, surgery, and histopathology of the gallbladder. Symptomatic improvement was assessed during routine 2-week postoperative visit and a follow-up phone interview. Thirty-two patients had undergone laparoscopic cholecystectomy during the study period for symptomatic hyperkinetic gallbladder. All the patients had abdominal pain related to food intake and 17 (53%) patients had worsening of symptoms with CCK infusion. The average GBEF was 92%. Chronic cholecystitis was seen in 29 (90%) patients on pathology. 23 (74%) patients had complete resolution of biliary symptoms, 5 (16%) had improved symptoms, and 3 (10%) had no change in symptoms. Patients with biliary colic and hyperkinetic gallbladder respond favorably to laparoscopic cholecystectomy. Our results suggest that patients with biliary colic in the setting of hyperkinetic gallbladder have symptomatic improvement following cholecystectomy.

Effect of Albiglutide on Cholecystokinin-Induced Gallbladder Emptying in Healthy Individuals: A Randomized Crossover Study.

The glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) exenatide and lixisenatide reduce cholecystokinin (CCK)-induced gallbladder emptying in healthy subjects. It is unknown if all GLP-1 RAs share this effect; therefore, the effect of the GLP-1 RA albiglutide on gallbladder function was assessed. In this randomized, double-blind, 2-way crossover study, a single dose of subcutaneous albiglutide 50 mg or placebo was administered to 17 healthy subjects, and CCK-induced gallbladder contractility was measured by ultrasonography. CCK (0.003 μg/kg) was infused intravenously over 50 minutes on study day 4 (3 days after dosing, to coincide with albiglutide's expected time to maximum concentration). Gallbladder volume, ejection fraction, and the main pancreatic and common bile-duct diameters were measured before, during, and following CCK infusion. Gallbladder volume was significantly greater in the albiglutide vs placebo groups before, during, and after CCK infusion, and the mean difference from placebo increased numerically during CCK infusion. The area under the volume-effect curve was significantly greater with albiglutide (P = .029). Starting at the 30-minute CCK infusion time point, the gallbladder ejection fraction was significantly lower with albiglutide than placebo. Changes in pancreatic duct diameter and common bile-duct diameter were not significantly different between albiglutide and placebo. Similar incidences of adverse events were observed between the albiglutide and placebo treatment periods. No new albiglutide safety signals were detected, and no serious adverse events were reported. In conclusion, similar to other GLP-1 RAs, albiglutide decreased CCK-induced gallbladder emptying compared with placebo in healthy individuals. Clinical implications of the gallbladder effects are unclear at this time.

Activation of galanin and cholecystokinin receptors in the lumbosacral spinal cord is required for ejaculation in male rats.

The spinal ejaculation generator is comprised of lumbar spinothalamic (LSt) cells and their axonal projections to autonomic and motor neurons in the lumbosacral spinal cord. LSt cells regulate ejaculatory reflexes by release of neuropeptides that are co-expressed in their axons, as previously demonstrated for gastrin-releasing peptide and enkephalin. Here, the role of two other neuropeptides co-expressed in LSt cells for ejaculatory reflexes is demonstrated: galanin and cholecystokinin (CCK). Adult male rats were anesthetized, spinalized, and received intrathecal infusions of galanin receptor antagonist Galantide (1 or 10nmol) or CCK receptor antagonist proglumide (71 or 714nmol). The dorsal penile nerve (DPN) was electrically stimulated to trigger ejaculatory reflexes and seminal vesicle pressure (SVP) and rhythmic contractions of the bulbocavernosus muscle (BCM) were analyzed as parameters of emission and expulsion respectively. Treatment with galanin or CCK antagonists significantly reduced SVP increases and BCM bursting, demonstrating that galanin and CCK are required for ejaculation. Next, anesthetized, spinalized males received intrathecal infusions of galanin (0.15 or 0.3nmol) or CCK(26-33) (4.35nmol) and effects on subthreshold DPN stimulations were determined. Intrathecal infusions of galanin or CCK facilitated ejaculatory reflexes induced by subthreshold DPN stimulation in all animals, but did not trigger ejaculatory reflexes in the absence of DPN stimulation. Together, these results demonstrate that galanin and CCK both act in the spinal ejaculation generator to regulate ejaculation. However, effects of galanin and CCK were dependent on DPN stimulation, suggesting that these neuropeptides may act in concert with other LSt co-expressed neuropeptides.

Cholecystokinin-Induced Gallbladder Emptying and Metformin Elicit Additive Glucagon-Like Peptide-1 Responses.

Bile acids have been suggested to mediate glucagon-like peptide-1 (GLP-1) secretion. Metformin, too, has been shown to increase GLP-1 levels. The effect of gallbladder emptying, metformin, or a combination has, however, never been studied. We hypothesized that cholecystokinin (CCK)-8-induced gallbladder emptying stimulates human GLP-1 secretion and that metformin would potentiate this effect. A double-blinded, randomized study. The study was conducted at a specialized research unit. Ten healthy male subjects with no family history of diabetes (age, 22 [range, 20-32] years; body mass index, 21.7 [19.3-24.2] kg/m(2); fasting plasma glucose, 4.9 [4.7-5.3] mm; and glycosylated hemoglobin A1c, 5.1 [4.4-5.8] %). On 4 separate days, the subjects received metformin or placebo and a concomitant 60-minute intravenous infusion of saline or CCK. Blood was sampled for 4 hours, and gallbladder volume was measured by ultrasound. Plasma levels of GLP-1. CCK-induced gallbladder emptying and metformin alone (no observed effect on gallbladder emptying) both elicited significant and additive GLP-1 responses. Metformin alone or combined with gallbladder emptying elicited a significant peptide YY response. CCK-induced gallbladder emptying resulted in a short-lasting glucose-dependent insulinotropic polypeptide response independent of metformin. No effects were seen on plasma glucose, insulin, C-peptide, or gastrin. CCK-induced gallbladder emptying in healthy subjects elicits significant GLP-1 secretion, which can be potentiated by metformin.

Role of capsaicin-sensitive peripheral sensory neurons in anorexic responses to intravenous infusions of cholecystokinin, peptide YY-(3-36), and glucagon-like peptide-1 in rats.

Cholecystokinin (CCK)-induced suppression of feeding is mediated by vagal sensory neurons that are destroyed by the neurotoxin capsaicin (CAP). Here we determined whether CAP-sensitive neurons mediate anorexic responses to intravenous infusions of gut hormones peptide YY-(3-36) [PYY-(3-36)] and glucagon-like peptide-1 (GLP-1). Rats received three intraperitoneal injections of CAP or vehicle (VEH) in 24 h. After recovery, non-food-deprived rats received at dark onset a 3-h intravenous infusion of CCK-8 (5, 17 pmol·kg⁻¹·min⁻¹), PYY-(3-36) (5, 17, 50 pmol·kg⁻¹·min⁻¹), or GLP-1 (17, 50 pmol·kg⁻¹·min⁻¹). CCK-8 was much less effective in reducing food intake in CAP vs. VEH rats. CCK-8 at 5 and 17 pmol·kg⁻¹·min⁻¹ reduced food intake during the 3-h infusion period by 39 and 71% in VEH rats and 7 and 18% in CAP rats. In contrast, PYY-(3-36) and GLP-1 were similarly effective in reducing food intake in VEH and CAP rats. PYY-(3-36) at 5, 17, and 50 pmol·kg⁻¹·min⁻¹ reduced food intake during the 3-h infusion period by 15, 33, and 70% in VEH rats and 13, 30, and 33% in CAP rats. GLP-1 at 17 and 50 pmol·kg⁻¹·min⁻¹ reduced food intake during the 3-h infusion period by 48 and 60% in VEH rats and 30 and 52% in CAP rats. These results suggest that anorexic responses to PYY-(3-36) and GLP-1 are not primarily mediated by the CAP-sensitive peripheral sensory neurons (presumably vagal) that mediate CCK-8-induced anorexia.

Prefrontal Cortical Circuit for Depression- and Anxiety-Related Behaviors Mediated by Cholecystokinin: Role of ΔFosB

Decreased medial prefrontal cortex (mPFC) neuronal activity is associated with social defeat-induced depression- and anxiety-like behaviors in mice. However, the molecular mechanisms underlying the decreased mPFC activity and its prodepressant role remain unknown. We show here that induction of the transcription factor ΔFosB in mPFC, specifically in the prelimbic (PrL) area, mediates susceptibility to stress. ΔFosB induction in PrL occurred selectively in susceptible mice after chronic social defeat stress, and overexpression of ΔFosB in this region, but not in the nearby infralimbic (IL) area, enhanced stress susceptibility. ΔFosB produced these effects partly through induction of the cholecystokinin (CCK)-B receptor: CCKB blockade in mPFC induces a resilient phenotype, whereas CCK administration into mPFC mimics the anxiogenic- and depressant-like effects of social stress. We previously found that optogenetic stimulation of mPFC neurons in susceptible mice reverses several behavioral abnormalities seen after chronic social defeat stress. Therefore, we hypothesized that optogenetic stimulation of cortical projections would rescue the pathological effects of CCK in mPFC. After CCK infusion in mPFC, we optogenetically stimulated mPFC projections to basolateral amygdala or nucleus accumbens, two subcortical structures involved in mood regulation. Stimulation of corticoamygdala projections blocked the anxiogenic effect of CCK, although no effect was observed on other symptoms of social defeat. Conversely, stimulation of corticoaccumbens projections reversed CCK-induced social avoidance and sucrose preference deficits but not anxiogenic-like effects. Together, these results indicate that social stress-induced behavioral deficits are mediated partly by molecular adaptations in mPFC involving ΔFosB and CCK through cortical projections to distinct subcortical targets.

Cholecystokinin from the entorhinal cortex enables neural plasticity in the auditory cortex

Patients with damage to the medial temporal lobe show deficits in forming new declarative memories but can still recall older memories, suggesting that the medial temporal lobe is necessary for encoding memories in the neocortex. Here, we found that cortical projection neurons in the perirhinal and entorhinal cortices were mostly immunopositive for cholecystokinin (CCK). Local infusion of CCK in the auditory cortex of anesthetized rats induced plastic changes that enabled cortical neurons to potentiate their responses or to start responding to an auditory stimulus that was paired with a tone that robustly triggered action potentials. CCK infusion also enabled auditory neurons to start responding to a light stimulus that was paired with a noise burst. In vivo intracellular recordings in the auditory cortex showed that synaptic strength was potentiated after two pairings of presynaptic and postsynaptic activity in the presence of CCK. Infusion of a CCKB antagonist in the auditory cortex prevented the formation of a visuo-auditory association in awake rats. Finally, activation of the entorhinal cortex potentiated neuronal responses in the auditory cortex, which was suppressed by infusion of a CCKB antagonist. Together, these findings suggest that the medial temporal lobe influences neocortical plasticity via CCK-positive cortical projection neurons in the entorhinal cortex.

Concurrent modulation of extracellular levels of noradrenaline and cAMP during stress and by anxiogenic- or anxiolytic-like neuropeptides in the prefrontal cortex of awake rats

The purpose of this study was to examine the effects of stress and the role of locally infused anxiogenic-like neuropeptides galanin, CCK-8, vasopressin, substance P and neurokinin A, and anxiolytic-like peptides NPY, nociceptin/orphanin FQ, somatostatin and neurotensin, on modulation of noradrenaline (NA) and cAMP efflux monitored simultaneously by microdialysis in the medial prefronatal cortex of awake rats. Concentrations of cAMP were determined by a newly developed method based on derivatization of cAMP with 2-chloroacetaldehyde followed by HPLC with fluorescence detection. Local infusion of forskolin (10 and 30μM) dose-dependently increased the cAMP levels to 417% and 1050% of the control group, respectively. Similarly, local infusion of NA (10μM) increased the cAMP to the peak level of 168%. A 5-min tail pinch and a 10-min swim stress rapidly increased the NA and cAMP levels to 167% and 203% (NA) and 141% and 161% (cAMP), respectively. Infusion of galanin and CCK-8 (0.5nmol, and 1.5nmol/0.5μl) dose-dependently increased NA to the peak levels of 191% and 179% and cAMP levels to 174% and 166%, respectively. The peak levels following infusions of vasopressin, substance P and neurokinin A were 91%, 135% and 86% for NA and 131%, 83% and 76% for cAMP, respectively. Infusions of anxiolytic-like peptides at highest concentrations significantly increased (NPY, 136%) or decreased (nociceptin, 71%; somatostatin, 86%) the NA levels, whereas neurotensin had no effect. The cAMP levels decreased to 86% (NPY, neurotensin), 78% (nociceptin), somatostatin infusion was without effect. The present findings confirmed a close correlation between the stress-induced increases in prefrontal cortical NA and cAMP levels, as well as, concurrent changes in NA and cAMP levels following infusions of galanin and CCK-8 (increased levels) and nociceptin/orphanin FQ (decreased levels). Infusions of other neuropeptides showed a more complex pattern of NA and cAMP responses.

Effect of cholecystokinin on rectal motor and sensory function in patients with irritable bowel syndrome and healthy controls

Ingestion of a meal frequently induces an urge to defaecate, the so-called gastro-colonic or gastro-rectal reflex. In patients with irritable bowel syndrome (IBS), symptoms are often provoked by meals. Cholecystokinin (CCK), a proximal gut peptide released after ingestion of a meal, may mediate these postprandial changes. The potential role of CCK in rectal sensory and motor function was evaluated by a rectal barostat study in healthy controls and patients with IBS. METHOD ; The sensory effects on serosal and mucosal receptors were studied. Twelve healthy controls and 12 patients with IBS underwent a ramp distension procedure of the rectum during infusion of CCK and placebo in random order. In 10 other healthy controls and 10 IBS patients an intermittent distension procedure was performed during infusion of CCK and placebo in random order. No differences were found in rectal compliance during ramp distensions between IBS patients and controls. CCK did not affect perception of urge and pain in controls or in IBS patients. Similar results were obtained during the intermittent distensions, but at higher distension pressures CCK significantly increased rectal sensitivity in IBS patients. Infusion of exogenous CCK to plasma levels normally seen in the postprandial state did not influence rectal motor function or sensations during ramp distension but it did significantly increase pain sensation in IBS patients during rapid intermittent distension.

Effect of exenatide on cholecystokinin-induced gallbladder emptying in fasting healthy subjects

Exenatide is a glucagon-like peptide-1 receptor agonist for the treatment of type 2 diabetes and has been shown to lower blood glucose through multiple mechanisms, including glucose-dependent insulin secretion, suppression of postprandial glucagon release and slowing of gastric emptying. The effects of exenatide on biliary motility are unknown. This study evaluated the effect of a single dose of exenatide on cholecystokinin (CCK)-induced gallbladder emptying. Healthy subjects participated in this randomized, 2-period, double-blind crossover study. Fasting subjects received a single subcutaneous injection of exenatide (10μg) or placebo 60min before CCK infusion. Gallbladder volume and ejection fraction (EF) were assessed by ultrasonography before, during, and after CCK infusion (0.003μg/kg infused over 50min at 2mL/min). The diameters of the main pancreatic duct and common bile duct were measured sonographically at the same time points before, during, and following CCK infusion. Administration of exenatide did not affect pre-CCK infusion gallbladder volume or EF compared to placebo. During the CCK-infusion, the mean minimum gallbladder volume was similar for exenatide (13.68mL) and placebo (11.05mL) (least squares mean [LSM] difference of 2.62mL; 95% confidence interval [CI], −0.53, 5.78), but the mean maximum EF was lower for exenatide (28.79%) versus placebo (46.13%) (LSM difference of −17.34%; 95% CI, −30.54, −4.13). Exenatide had no clinically significant effects on pancreatic or bile duct diameters. In conclusion, exenatide reduced CCK-induced gallbladder emptying compared with placebo in fasting healthy subjects.

Normokinetic biliary dyskinesia: a novel diagnosis

Biliary dyskinesia diagnosed with CCK-HIDA scan and ejection fraction less than 35 % has been successfully treated by laparoscopic cholecystectomy. However, a population of patients with symptomatic biliary pain and a normal CCK-HIDA scan never receive a diagnosis, and thus no definitive treatment. Some of these patients report a reproducible pain during their CCK-HIDA scan. It is hypothesized that these patients have a novel diagnosis, normokinetic biliary dyskinesia, and may have resolution of pain when treated with cholecystectomy. A retrospective chart review was completed looking for patients with biliary pain in accordance with the ROME III criteria. Additional inclusion criteria were (1) greater than age 18 years, (2) reproducible biliary symptoms during the CCK-HIDA scan, and (3) an ejection fraction greater than 35 %. Treatment modality was laparoscopic cholecystectomy. Descriptive statistics were preformed, and data were reported as mean ± standard deviation and range. Nineteen patients met the inclusion criteria for this study from August 2008 to July 2011. There were 15 women and 4 men with a mean age of 48.4 ± 13.0 years. The mean ejection fraction was 75.1 ± 19.4 %. The average duration of preoperative symptoms was 6.8 ± 5.9 months and postoperative follow-up was 21.8 ± 10.6 months. Seventeen patients had complete resolution of symptoms, one had partial resolution, and one had no change. There was a complete resolution rate of 89.5 % and an improvement rate of 94.7 %. We suggest that patients who present with biliary pain, a normal CCK-HIDA scan with an ejection fraction greater than 35 %, and with reproducible symptoms on infusion of CCK could have a novel diagnosis: normokinetic biliary dyskinesia. Currently, these patients are excluded from the diagnosis of biliary dyskinesia and thus treatment. We hypothesize a potential new diagnosis, suggest cholecystectomy as treatment, and recommend a prospective study design for further evaluation.

Endoscopic pancreatic function test using combined secretin and cholecystokinin stimulation for the evaluation of chronic pancreatitis

Current endoscopic pancreatic function test (ePFT) methods use either secretin or cholecystokinin (CCK) to measure pancreatic function. To evaluate a novel ePFT protocol that includes both secretin and CCK stimulation and to assess which fluid parameters best discriminate patients with chronic pancreatitis (CP). Prospective, cross-sectional diagnostic study. Single, tertiary-care institution. Healthy volunteers and patients evaluated for CP were included. All patients underwent a combined secretin-CCK ePFT. Patients evaluated for CP also underwent EUS during the same endoscopic session. Duodenal fluid bicarbonate, lipase, and amylase concentrations were measured after CCK and secretin stimulation. Results were compared based on the presence of CP detected by EUS (≥5 features). Twenty healthy volunteers and 69 patients evaluated for CP completed the secretin and CCK ePFT. Patients with an EUS score of 5 or higher had significantly decreased peak bicarbonate concentrations (72 mmol) compared with patients with an EUS score lower than 5 (90 mmol) and healthy subjects (108 mmol) (P < .001). Peak concentrations of amylase and lipase and total fluid volume were not significantly different between patients with CP and controls. Receiver-operating characteristic analysis revealed that peak bicarbonate concentration had superior discrimination for CP (area under the curve [AUC] 0.738) compared with peak amylase (AUC 0.677) and peak lipase (AUC 0.627). The addition of enzyme concentration measurement did not improve discrimination compared with peak bicarbonate alone. Secretin and cholecystokinin endoscopic pancreatic function test (SC ePFT) results were not compared with those of single hormone ePFTs. The addition of CCK infusion and enzyme concentration measurement to a standard secretin ePFT does not enhance the diagnosis of CP.

Cholecystokinin enhances visceral pain-related affective memory via vagal afferent pathway in rats

BackgroundPain contains both sensory and affective dimensions. Using a rodent visceral pain assay that combines the colorectal distension (CRD) model with the conditioned place avoidance (CPA) paradigms, we measured a learned behavior that directly reflects the affective component of visceral pain, and showed that perigenual anterior cingulate cortex (pACC) activation is critical for memory processing involved in long-term visceral affective state and prediction of aversive stimuli by contextual cue. Progress has been made and suggested that activation of vagal afferents plays a role in the behavioral control nociception and memory storage processes.In human patients, electrical vagus nerve stimulation enhanced retention of verbal learning performance. Cholecystokinin-octapeptide (CCK), which is a gastrointestinal hormone released during feeding, has been shown to enhance memory retention. Mice access to food immediately after training session enhanced memory retention. It has been well demonstrated that CCK acting on vagal afferent fibers mediates various physiological functions. We hypothesize that CCK activation of vagal afferent enhances visceral pain-related affective memory.ResultsIn the presented study, infusion of CCK-8 at physiological concentration combining with conditional training significantly increased the CRD-induced CPA scores, and enhanced the pain affective memory retention. In contrast, CCK had no effect on CPA induced by non-nociceptive aversive stimulus (U69,593). The physiological implications were further strengthened by the similar effects observed in the rats with duodenal infusion of 5% peptone, which has been shown to induce increases in plasma CCK levels. CCK-8 receptor antagonist CR-1409 or perivagal application of capsaicin abolished the effect of CCK on aversive visceral pain memory, which was consistent with the notion that vagal afferent modulates affective aspects of visceral pain. CCK does not change the nociceptive response (visceral pain sensitivity) and anterior cingulate cortex neuronal responses to CRD.ConclusionCCK activating vagal afferent C fibers enhances memory consolidation and retention involved in long-term visceral negative affective state. Thus, in a number of gastrointestinal disorders, such as irritable bowel syndrome, nutrient content may contribute to painful visceral perception by enhancing visceral aversive memory via acts on vagal afferent pathway.