Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027497 (nausea)
 23,468 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It is unclear whether behavioral depression and suppression of food intake by cholecystokinin (CCK) is contributed to by aversive gastrointestinal effects such as nausea. In the present study we examined the effect of a new antiemetic agent, ondansetron, a specific antagonist of 5-HT3 receptors, on suppression of variable-interval self-stimulation by the CCK analogue caerulein. Responding by rats for brain-stimulation reward is especially sensitive to CCK, and provides a convenient means of investigating this question. Caerulein (30 micrograms/kg, s.c.), injected alone, was followed by a profound (ca. 80%) reduction in the rate of self-stimulation, lasting about 30 min. Ondansetron (1.0-1000 micrograms/kg, s.c.) injected on its own had no effect on self-stimulation rate, and a 100-micrograms/kg dose did not lessen the depressant action of caerulein. The behavioural depressant effects of CCK are thus unlikely to depend on brain mechanisms for nausea and vomiting involving 5-HT3 receptors.
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PMID:Effect of the 5-HT3 receptor antagonist ondansetron on hypothalamic self-stimulation in rats and its interaction with the CCK analogue caerulein. 140 94

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

Clues to the pathogenesis of functional pain syndromes may be derived from the study of stimuli that precipitate or aggravate symptoms. In this study, cholecystokinin octapeptide (CCK-8, 0.06 microgram/kg) and placebo were given by intravenous infusion (5 min) in random order to control subjects and four groups of patients with unexplained abdominal pain. Induction of pain and nausea were assessed by linear analogue scales while sympathoadrenomedullary responses were assessed by serial changes in plasma concentrations of noradrenaline, adrenaline and dopamine. Scores for pain and nausea were low after infusion of placebo. After infusion of CCK-8, pain scores were significantly higher in patients with spontaneous pain than in control subjects, but significant increases in nausea were restricted to patients with irritable bowel syndrome and a subgroup of patients with pain after cholecystectomy. Although some groups showed increases in plasma concentrations of catecholamines after the infusion of CCK-8, the size of these increases was neither consistent among patients within each group nor predictive of scores of pain and nausea in individual subjects. Pain during the infusion of CCK-8 was a feature common to patients with diverse functional pain syndromes, and did not appear to be attributable to activation of the sympathetic nervous system.
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PMID:Responses to cholecystokinin octapeptide in patients with functional abdominal pain syndromes. 161 Oct 17

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

Antagonists of 5-hydroxytryptamine type 3 (5HT3) receptors reduce the nausea induced by cisplatinum, but the effects of these agents on 5HT3 receptors in the human gut remain to be defined. We examined the actions of one of these drugs (Glaxo GR 38032F) on small intestinal transit and mouth-to-cecum transit times in healthy man. We also quantified its effects on the release of peptide YY (PYY), neurotensin, human pancreatic polypeptide, gastrin-cholecystokinin, and motilin. Ten healthy volunteers were enrolled in a randomized, double-blind, placebo-controlled crossover study. Following a single intravenous dose of GR 38032F (0.15 mg/kg), we measured the time to appearance in plasma of sulfapyridine after injection of salicylazosulfapyridine into the duodenum. This was used as a measure of duodenocecal transit. The appearance of hydrogen in breath after ingestion of a meal containing lactulose was also correspondingly used to quantify the mouth-to-cecum transit of the "head" of the meal. Gastrointestinal hormones were assayed in plasma by specific RIAs; samples were drawn fasting (10 min after injection) and after breakfast (358 calories: 15.7 g protein, 55.4 g carbohydrate, 8.1 g fat). The postprandial integrated response and peak release of PYY was decreased by GR 38032F. There was also a trend for the peak release of neurotensin to be reduced. GR 38032F did not significantly alter small intestinal transit times or mouth-to-cecum transit times. We conclude that GR 38032F does not have a major effect on small intestinal transit in health.
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PMID:Effect of selective 5HT3 antagonist (GR 38032F) on small intestinal transit and release of gastrointestinal peptides. 252 8

We have investigated the role of the area postrema (AP) in mediating the neurohypophyseal hormone response to peripheral administration of nausea-producing agents in rats. In control animals, lithium chloride (LiCl) and apomorphine (APO) caused a rise in plasma levels of immunoreactive oxytocin (OT) and arginine-vasopressin (AVP), whereas sulphated cholecystokinin octapeptide (CCK-8s) stimulated OT secretion only. Rats with AP lesions exhibited a similar OT and AVP response to LiCl and APO but the OT response to CCK-8s was significantly diminished. The results indicate that the selective stimulation of OT secretion by CCK-8s is partly mediated via the AP. Although the nausea-producing effects of LiCl and APO may involve the AP, the neuroendocrine effects of these agents may well be mediated via actions outside the AP.
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PMID:A role for the area postrema in mediating cholecystokinin-stimulated oxytocin secretion. 282 55

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

Administration of lithium chloride and copper sulfate to adult monkeys caused marked elevations in plasma vasopressin (AVP) levels without significant increases in plasma oxytocin (OT) levels. Emesis was produced in five of the seven animals given these agents, in support of nausea as the main stimulus to AVP release. A similar pattern of AVP release without OT release was found after administration of cholecystokinin (CCK). Although most monkeys vomited in response to 10 micrograms/kg of CCK, a significant increase in plasma AVP levels also was produced with a dose of 1 microgram/kg, which did not produce emesis in any animal. These findings are in marked contrast with previous results in rats, which indicated that lithium chloride, copper sulfate, and CCK each stimulated OT rather than AVP release. Despite this interspecies difference, the significant neurohypophysial hormone secretion in response to both nausea-producing agents and CCK suggests that AVP secretion in monkeys, similar to OT secretion in rats, might reflect activation of central pathways mediating nausea and/or inhibition of food intake, even when overt illness is not produced.
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PMID:Vasopressin release in response to nausea-producing agents and cholecystokinin in monkeys. 303 8


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