Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0042963 (vomiting)
 31,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The satiety effect of slow intravenous infusions of impure cholecystokinin (CCK) was investigated in 5 rhesus monkeys during sham feeding. CCK suppressed sham feeding. The dose for 50% inhibition of sham feeding was about 10 U/kg-hr; 20 U/kg-hr abolished sham feeding. No dose produced retching, vomiting, diarrhea or other behavioral signs of toxicity. These results demonstrate the potency of CCK for inhibiting feeding in the monkey when gastric, intestinal and postabsorptive mechanisms are not activated by ingested food.
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PMID:Cholecystokinin suppresses sham feeding in the rhesus monkey. 11 72

We investigated the role of adrenergic receptors in the mechanisms of initiation of vomiting and its gastrointestinal (GI) motor correlates. The effects of clonidine, UK-14304, St-91, naphazoline, phenylephrine and isoproterenol were examined for their ability to initiate vomiting and its GI motor correlates. Only the alpha-2 adrenoceptor agonists UK-14304, clonidine, St-91 and naphazoline activated vomiting and its GI motor correlates. Tolerance of vomiting, but not its GI motor correlates, readily developed to all alpha-2 adrenergic receptor agonists but St-91. The responses to UK-14304 or clonidine were blocked by idazoxan, yohimbine, clonidine tolerance or high doses of phenoxybenzamine, but not by propranolol or prazosin. The responses to UK-14304 or clonidine were also blocked by fentanyl, 1-(1-naphthyl) piperazine, methysergide, SCH 22390 or scopolamine, but not by haloperidol, sulpiride, domperidone or naloxone. Adrenoceptor antagonists, clonidine tolerance or sympathetic blockade did not block vomiting or its GI motor correlates activated by apomorphine, CuSO4 or cholecystokinin-octapeptide. We concluded that alpha-2 adrenergic receptors of the chemoreceptive trigger zone can initiate vomiting and its GI motor correlates, but these receptors do not mediate vomiting induced by another chemoreceptive trigger zone stimulant, apomorphine, or stimulation of the GI tract using CuSO4. However, 5-hydroxytryptamine-2 serotonergic, muscarinic cholinergic and opiate receptors within the central nervous system participate in controlling emesis activated by alpha-2 adrenergic agonists. Peripheral adrenergic receptors do not mediate the GI motor correlates of vomiting.
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PMID:The role of adrenergic receptors in the initiation of vomiting and its gastrointestinal motor correlates. 135 60

In a variety of in vivo and in vitro tests, cholecystokinin (CCK) has been shown to produce effects that would suggest a functional antagonism of dopamine. On that basis, it has been hypothesized that CCK could have antipsychotic effects. We compared the CCK agonist, A68552, to the antipsychotics haloperidol (HAL), clozapine (CLOZ) and sulpiride (SULP) in various forms of conditioned avoidance using rats, mice, and cynomolgus monkeys. In rats, HAL disrupted both acquisition of a conditioned shelf-jump avoidance response and performance of the response by previously trained animals. CLOZ and SULP were ineffective in suppressing performance by previously trained rats but blocked acquisition of the response. CLOZ disrupted avoidance responding on the first 3 of 4 consecutive days of acquisition. SULP significantly suppressed avoidance responding on the last 3 days and significantly increased escape failures on day 2. A68552 administered during acquisition failed to significantly suppress avoidance responding. In mice, both HAL and CLOZ blocked performance of two-way shuttle conditioned avoidance at doses (0.1 and 3.0 mg/kg, IP, respectively) that had no effect on escape responding. A68552 at doses up to 1.07 mg/kg IP had no effect on performance. Mice treated with A68552 during acquisition showed a mild but statistically significant suppression of avoidance and an equivalent suppression of escape responding. Cynomolgus monkeys trained in a conditioned avoidance procedure were sensitive to the disruptive effects of HAL at a dose of 0.03 mg/kg IM while A68552 was without significant effect at doses up to those producing emesis (0.214 mg/kg, IM). A68552 does not resemble either HAL or the "atypical" antipsychotics, CLOZ or SULP, in conditioned avoidance tests.
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PMID:Evaluation of a stable CCK agonist (A68552) in conditioned avoidance responding in mice, rats, and primates: comparison with typical and atypical antipsychotics. 135 71

MK-329 is a nonpeptidal, highly specific cholecystokinin (CCK) receptor antagonist, with affinity for pancreatic and gallbladder CCK receptors similar to CCK itself. MK-329 and its progenitor, asperlicin, can inhibit the growth of CCK receptor-positive human pancreatic cancer in athymic mice. Based on these activities and the ability of MK-329 to transiently increase food intake and enhance morphine analgesia in murine models, we conducted an open trial of MK-329 in 18 patients with advanced pancreatic cancer in whom the CCK receptor status of the tumors was unknown. Tumor response, pain control, and nutritional parameters (hunger rating, caloric intake, body weight, and anthropometrics) were serially assessed. The results of the study failed to demonstrate any impact of MK-329 on tumor progression, pain, or nutrition. Toxicity was mild and limited to nausea, vomiting, diarrhea, and abdominal cramps, with 17 of 18 patients able to tolerate treatment. While a role for MK-329 in the management of patients with advanced pancreatic cancer cannot be supported by the results of this trial, additional studies of this agent in patients with known CCK receptor-positive tumors, at escalated doses, and possibly in conjunction with other growth antagonists, appear warranted.
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PMID:A pilot clinical trial of the cholecystokinin receptor antagonist MK-329 in patients with advanced pancreatic cancer. 155 66

Substance P is a 11 amino-acids peptide which belongs to the tachykinins, a family of peptide which induces a rapid contraction of the smooth muscle of the digestive tract. The occurrence of substance P has been demonstrated by immunohistochemical and radioimmunological techniques in most parts of the central and peripheral nervous system. Substance P exerts on the smooth muscle of all the areas of the digestive tract a strong excitatory effect which is either direct or relayed by the cholinergic intramural neurones. Numerous electrophysiological, pharmacological and immunohistochemical data lead to the conclusion that substance P is released by intrinsic neurones of the digestive tract or by extrinsic nerves (vagus and splanchnic nerves, etc...). This release is enhanced by acetylcholine, cholecystokinin, serotonin and neurotensin, it is reduced by opioid peptides and noradrenaline. Substance P participates in the intestinal peristaltic reflex by the activation of the smooth muscle cells of the intestine, either directly or through the activation of the cholinergic intrinsic neurones. Substance P is also involved in the genesis of a non-cholinergic ascending excitatory activity likely occurring during vomiting. Lastly, substance P participates in the reflex contraction of the lower oesophageal sphincter following acidification of the distal part of the oesophagus.
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PMID:[Role of substance P in the nervous system control of digestive motility]. 172 Jun 93

Hunger and satiety appear to reflect the postabsorptive and absorptive phases of caloric homeostasis, respectively. However, only some of the signals that inhibit food intake can be related to caloric homeostasis. For example, decreases in food intake also are observed after administration of nauseogenic chemical agents, treatment with cholecystokinin (CCK), or dehydration. In each case, inhibition of food intake is correlated with induced decreases in gastric motility and increases in secretion of pituitary oxytocin in rats; in primates, including humans, vasopressin but not oxytocin is secreted. In contrast, meal-induced satiety increases gastric contractions and has little or no effect on neurohypophyseal hormone secretion in rats or human subjects. Nauseogenic toxins, CCK, and dehydration stimulate very different subjective states from satiety: LiCl elicits abdominal cramps, nausea, and vomiting, as does exogenous CCK in high doses, whereas dehydration elicits thirst. Thus, inhibition of eating may not be associated with satiety or reflect changes in caloric flux; noncaloric controls of food intake exist and may be accompanied by distinctive increases in neurohypophyseal hormone secretion and loss of gastric function.
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PMID:Caloric and noncaloric controls of food intake. 195 22

The newly recognized class of 5-hydroxytryptamine receptors (5HT3) may be involved in the induction of nausea, since their pharmacological antagonists are effective against emesis induced by chemotherapy. 5HT3 receptors are present on enteric neurons, and 5HT3 blockers may produce mild constipation; we thus hypothesized that 5HT3 receptors would modulate colonic motility. To determine if GR 38032F, a selective 5HT3 antagonist known to have antiemetic effects, influences colonic transit in health, a randomized, double-blind, placebo-controlled crossover study was performed. Using a radiopaque marker technique, colonic transit was quantified in 39 healthy volunteers (19 men, 20 nonpregnant women) 18-70 years of age. On a standard 25-g fiber diet, 16 mg of GR 38032F was given orally thrice daily. Gastrointestinal peptides (peptide YY, human pancreatic polypeptide, neurotensin, motilin, gastrin-cholecystokinin, substance P) were also measured in plasma fasting and postprandially. Mean total colonic transit time on placebo was 27.8 hr, while on GR 38032F it was 39.1 hr (P less than 0.0005). Transit times through the left colon (P less than 0.0005) and rectosigmoid (P less than 0.05) were prolonged by the drug, but right colonic transit was not significantly altered. Transit times did not correlate with age or gender, but subjects with shorter transit times were significantly more affected than were those with longer transit times. The peak release of peptide YY was minimally decreased following GR 38032F (P less than 0.01), but the peak and integrated postprandial responses of human pancreatic polypeptide, neurotensin, motilin, gastrin-cholecystokinin, and substance P were not significantly altered by the drug.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:GR 38032F (ondansetron), a selective 5HT3 receptor antagonist, slows colonic transit in healthy man. 213 32

The effect of duodenal osmoreceptor stimulation on gallbladder motility was evaluated in 18 normal subjects during intraduodenal infusion of 280, 560 and 840 mosm/liters NaCl solutions. Gallbladder emptying was found to be dose-dependent between 560 and 840 mosm/liter (P less than 0.01 vs basal volume). The effect of duodenal infusion of hypertonic saline on gallbladder emptying was prevented by atropine and partially antagonized by naloxone, indicating that cholinergic and endorphinergic pathways may be involved in regulating this reflex. Since proglumide, a cholecystokinin (CCK) antagonist, did not affect gallbladder emptying induced by hypertonic saline, it seems likely that CCK is not released by increasing duodenal osmolality. A significant reduction in gallbladder volume was obtained when hyperosmolar saline was delivered into the duodenum, whereas no emptying was seen when infused into the gastric antrum or the jejunum, suggesting that osmoreceptors that activate gallbladder emptying are located only in the duodenum. Additionally, all subjects manifested central symptoms (nausea or vomiting) during duodenal infusion of hypertonic saline, suggesting that central mechanisms might be activated by a change in duodenal osmolality. Our data indicate that the osmolality of duodenal contents might regulate gallbladder motility by neural atropine- and naloxone-sensitive pathways.
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PMID:Duodenal osmolality drives gallbladder emptying in humans. 234 3

The gastrointestinal motor correlates of vomiting consist of two contractile events, 1) a giant retrogradely propagated contraction of the upper small intestine, the retrograde giant contraction (RGC) and 2) a series of post-RGC phasic contractions that occur primarily in the lower small intestine. The effects of cholinergic, dopaminergic, serotonergic, and opioid receptor antagonists and an opioid receptor agonist on vomiting and its gastrointestinal motor correlates initiated by apomorphine (APO), CuSO4, or cholecystokinin octapeptide (CCK-8) were determined in awake dogs. Atropine blocked the retrograde giant contraction only, and hexamethonium blocked all jejunoileal motor responses activated by APO, CuSO4, or CCK-8. Domperidone blocked all effects of APO only, whereas haloperidol, methysergide, 1-(1-naphthyl) piperazine, and fentanyl blocked or inhibited responses to both APO and CuSO4. None of the dopaminergic, serotonergic, or opioid receptor antagonists or the opioid receptor agonist affected the gastrointestinal motor responses to CCK-8. Cinanserin or Sch 23390 had no effect on any of the responses activated by APO, CuSO4, or CCK-8. These results suggested that D2 dopaminergic and 5-HT2 serotonergic receptors of the emetic central pattern generator mediate vomiting and its gastrointestinal motor correlates, whereas opioid receptors may mediate tonic inhibition of these responses. In addition, peripheral muscarinic or nicotinic cholinergic receptors but not peripheral 5-HT2, dopaminergic, or opioid receptors mediate the gastrointestinal motor correlates of vomiting.
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PMID:Functional localization of specific receptors mediating gastrointestinal motor correlates of vomiting. 256 2

Exogenous administration of cholecystokinin octapeptide (CCK) is known to decrease food intake and slow gastric emptying in humans and animals. Recent studies have shown that CCK stimulates neurohypophyseal secretion of oxytocin (OT) in rats and arginine vasopressin (AVP) in monkeys, and that gastric distention also stimulates OT release in rats. We therefore studied AVP and OT secretion in 14 normal subjects in response to meal-induced gastric distention and administration of CCK, both separately and in combination, to assess whether these stimuli similarly activated central neurohypophyseal pathways in humans. Neither plasma AVP nor OT concentrations increased after gastric distention produced by ingestion of a large meal. However, a dose-related increase in plasma AVP, but not OT levels, occurred after CCK administration, the threshold CCK dose being 0.05 micrograms/kg body weight. The AVP secretion in response to CCK administration was significantly correlated with subjective aversive symptoms quantified by use of a numeric scale (r = 0.61, P less than 0.001). In 12 of the 14 subjects plasma AVP levels increased in association with symptoms of epigastric pressure and discomfort before the onset of overt nausea or emesis. The combination of CCK and meal-induced gastric distention did not stimulate increases in plasma AVP levels in excess of those produced by CCK administration alone. The results demonstrate that AVP secretion resulting from emetic center activation often is a graded response that can begin in association with milder degrees of visceral discomfort before symptoms of overt nausea or emesis. In addition, the stimulation of AVP secretion by CCK administration, but not by meal-induced gastric distention in association with physiological satiety, suggests that some component of the anorectic effects of exogenous CCK in man likely results from activation of brainstem emetic centers.
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PMID:Neurohypophyseal secretion in response to cholecystokinin but not meal-induced gastric distention in humans. 292 13


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