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Role of the autonomic nervous system in emetic and cardiovascular responses in Suncus murinus.

To clarify the role of the autonomic nervous system in cardiovascular and emetic responses, we studied the influence of drugs that act on autonomic nervous function on emetic and cardiovascular responses induced by chemical or mechanical stimulation to the stomach in two strains of Suncus murinus, Jic:SUN-Her and Jic:SUN-Ler. Latency to the first retching in Jic:SUN-Her was significantly shorter than that in Jic:SUN-Ler to both mechanical and chemical stimulation. This result indicated that there are different sensitivities to mechanical and chemical stimulation to the stomach in these two strains of suncus. However, the numbers of emetic episodes were almost the same in these two strains. Mean blood pressure significantly increased from baseline prior to retching in both strains. Heart rate decreased in Jic:SUN-Her and increased in Jic:SUN-Ler prior to retching, suggesting that a different baroreflex responsiveness might exist in these two strains of suncus. Administration of acetylcholine and phenylephrine affected emetic response induced by mechanical and chemical stimulation. Although the baseline values of mean blood pressure and heart rate after administration of these drugs were different, changes in mean blood pressure and heart rate prior to retching were unaffected. This result suggested that the state of autonomic activity before the emetic response might be important in the development of the emetic response. Pretreatment with hexamethonium suppressed the cardiovascular response prior to retching and prolonged the latency to the first retching. This result indicated that there was an interaction between the mechanisms involved in cardiovascular and emetic responses. The change in autonomic function during the emetic response, especially enhancement of sympathetic activity prior to retching, may be relevant to emetic and cardiovascular responses. Moreover, these results suggest that different autonomic function or different baroreflex responsiveness in Jic:SUN-Her and Jic:SUN-Ler may be involved in emetic responses.

Acetylcholine↗

Enkephalin receptors in the emetic chemoreceptor trigger zone of the dog.

1 The emetic action of Met-enkephalin, morphine and naloxone was studied following their administration into the cerebral ventricles of dogs through chronically implanted cannulae and the effect on the responses of ablating the chemorceptor trigger zone (CTZ) was investigated. The opiate antagonist, naloxone, was used to determine the role of enkephalin receptors in emetic responses.2 Administration of Met-enkephalin (1.0 mug/kg) into the IVth ventricle regularly evoked emesis with an average latency of 35 s. A dose of morphine (2.5 mug/kg) which was five times larger was required for a consistent emetic response when introduced into the lateral cerebral ventricle (i.c.v.) as compared to the dose required by the IVth ventricular route. The latency of emetic responses by the latter route of injection of morphine was shorter. This is in accord with an action of morphine on the emetic CTZ.3 After bilateral ablation of the CTZ, intraventricular injections of Met-enkephalin and morphine failed to produce emesis even when given in doses that were 5 to 10 times the dose which regularly elicited emesis in animals with intact CTZ. The emesis produced in dogs by intraventricular Met-enkephalin and morphine is thus fully accounted for by an action on the CTZ.4 Naloxone (i.c.v.) in doses up to 10.0 mug/kg did not cause emesis. However, higher doses of naloxone elicited dose-dependent emesis in dogs. The 100% emetic dose of naloxone was found to be 160 mug/kg and the latency of emesis was 180 s. Unlike Met-enkephalin and morphine, naloxone continued to elicit emesis in CTZ-ablated animals.5 Pretreatment with intraventricular naloxone (1 to 8 mug/kg) blocked the emetic responses induced by intraventricular Met-enkephalin and morphine but not that to apomorphine. The selective protective action of the opiate antagonist against Met-enkephalin and morphine supports the presence of enkephalin receptors in the emetic CTZ.

Animals↗

Effects of droperidol dosage on postoperative emetic symptoms following pediatric strabismus surgery.

STUDY OBJECTIVE: To compare the frequency of postoperative emetic symptoms and side effects in pediatric strabismus surgery using four doses of droperidol. DESIGN: Randomized, blinded study. SETTING: University eye institute. PATIENTS: 82 ASA physical status I and II pediatric patients, aged 1 to 16 years, undergoing outpatient strabismus surgery. INTERVENTIONS: Patients were assigned to one of four doses of droperidol (10, 20, 40, or 80 microg.kg(-1)) (Groups 1, 2, 3, and 4, respectively). All patients received the same anesthetic management, with droperidol administered intravenously immediately after induction of anesthesia. MEASUREMENTS AND MAIN RESULTS: Postoperatively, patients were evaluated for emetic symptoms (nausea, retching, and/or vomiting) and side effects (postoperative sedation or extrapyramidal symptoms). There was a dose-dependent reduction of emetic symptoms seen with increasing droperidol dose. Predischarge emetic symptoms were 50%, 15%, 15%, and 5% in Groups 1, 2, 3, and 4, respectively (p < 0.009). Peak emetic symptoms were observed after discharge: 75%, 40%, 35%, and 15% in Groups 1, 2, 3, and 4, respectively (p < 0.003). Convalescence times, including awakening, extubation, recovery, and hospitalization, were unaffected by increasing droperidol dose. Sedation was similar in all groups and no patient exhibited any side effects. However, when patients exhibited emetic symptoms, discharge time increased from 207 +/- 57 minutes to 283 +/- 128 minutes (p < 0.001). CONCLUSIONS: Prophylactic administration of droperidol 80 microg.kg(-1) is most effective in reducing postoperative emetic symptoms without increasing time to discharge. In those patients with emetic symptoms who also received prophylactic droperidol, time to discharge was significantly delayed.

Adolescent↗

[Anti-emetic effect of ethanol extract from "Wuzhuyu broth"].

OBJECTIVE: To investigate the anti-emetic effect of ethanol extract from "WuZhuYu broth" and its mechanism. METHOD: Three experiments were carried out test which extract has anti-emetic activity, such as CuSO4-induced pigeon's emetic response, gastric emptying in mice and ACh-induced or 5-HT-induced contraction in vitro gastric muscle in rats. Meanwhile, effect of anti-emetic extract on concentration-response curve to ACh, 5-HT, histamine was investigated. RESULT: 50% ethanol extract and 70% ethanol extract were identified as having significantly stronger anti-emetic activities with little side effect, which showed the significant effect on concentration-response curve to ACh, 5-HT, histamine. CONCLUSION: 50% ethanol extract and 70% ethanol extract contain more anti-emetic fractions, more anti-emetic fractions can be gained at the concentrations of 50% and 70% ethanol; the mechanism of anti-emetic effect is related to its antagonism to the receptors of ACh, 5-HT, histamine.

Animals↗

Modulation of emetic response by carotid baro- and chemoreceptor activations.

We hypothesized that baroreceptor or chemoreceptor activation might be involved in the emetic, and prodromal cardiovascular and respiratory responses. To test this hypothesis, we induced the emetic responses by gastric distension in anesthetized Suncus murinus (house musk shrew), that had intact and absent baroreceptor and chemoreceptor afferents. Secondly, we stimulated the aortic depressor nerve (ADN) and the carotid sinus nerve (CSN) with or without gastric distension. Internal carotid artery ligation in the bifurcation area, which abolished reflex bradycardia by baroreceptor activation, and abolition of chemoreceptor reflex bradycardia and hyperventilation, by carotid body denervation, suppressed the emetic response but did not abolish it. ADN denervation, which produced no significant effects on the baroreceptor or chemoreceptor reflex bradycardia, had no effect on the emetic response, including the prodromal phase. CSN stimulation with gastric distension elicited retching accompanied by reflex bradycardia and hypotension during or just after stimulation, whereas ADN stimulation with gastric distension did not induce the cardiovascular reflex, and had no effects on the emetic response. These results indicate that carotid, rather than aortic, baroreceptor or chemoreceptor activation plays an important role in the augmentation of cardiac parasympathetic activity and the development of emetic response. In conclusion, carotid baroreceptor or chemoreceptor activation, which is non-emetic stimulation, acts as a modulator in the central mechanisms of emesis.

Animals↗

Biphasic emetic response of cyclophosphamide in the ferret.

Cyclophosphamide (177 mg/kg, IV: n = 8) produced a biphasic emetic response in the ferret with a mean +/- SE of 23.3 +/- 4.0 emetic episodes during a 4-h observation period. The emetic profile of cyclophosphamide showed a first phase with 18.6 +/- 3.9 episodes and a second phase with 4.7 +/- 1.2 episodes. Ondansetron (0.07 and 0.13 mg/kg, IV) and droperidol (0.25 and 0.79 mg/kg, IV) significantly reduced the number of emetic episodes in the first phase. Metoclopramide (2.24, 4.08, and 7.07 mg/kg, IV) also significantly reduced the number of emetic episodes in the first phase, and the dose of 7.07 mg/kg completely prevented emetic episodes in the second phase. In addition, ondansetron-treated ferrets (0.04, 0.07, and 0.13 mg/kg, IV) had a significant increase in the number of emetic episodes in the second phase.

Animals↗

The inhibitory effect of halothane on the emetic response in the ferret.

Emesis and nausea are often associated with anaesthesia and continue to be a common clinical problem. Past clinical studies have demonstrated that halothane produces a higher incidence of vomiting compared with other anaesthetics, but some investigators have described an antiemetic effect. The purpose of this study was to investigate the effects of various doses of halothane on the emetic response in the decerebrate ferret. Following a control emetic response, a maximum of six increasing cumulative concentrations of halothane were delivered. At the end of each delivery period, the supradiaphragmatic vagal communicating branch, which has been shown to reproducibly elicit vomiting, was electrically stimulated and the emetic response was monitored. An increase in halothane concentration produced a marked depression of tongue, abdominal muscle, and diaphragm EMG activity as well as a decrease in central venous pressure. Licking, a prodromal response comparable to nausea in the human, appeared to be most sensitive. An increase in latency of the emetic response occurred as the concentration of halothane was increased. All phases of the response were observed at concentrations below 0.6 vol% halothane. At 0.6 vol% halothane, 75% of the animals vomited. At higher concentrations, the emetic response was completely abolished. One hour post-halothane, all latencies had returned to near control values. The methods utilized in this study provided a model that was not complicated by a large number of variables usually present in clinical studies. These data demonstrate that halothane exerts an inhibitory, concentration-dependent, and reversible effect on the emetic response in the ferret and provide further support that halothane alone does not possess emetic properties at clinical properties at clinical concentrations.

Animals↗

Study of the effect of standardized chemotherapy order forms on prescribing errors and anti-emetic cost.

OBJECTIVES: Many anti-neoplastic medication errors and excessive use of serotonin antagonist anti-emetic agents might be prevented by the use of a standardized chemotherapy order form (SCOF). Several studies showing a reduction in prescribing errors or control of inappropriate anti-emetic use through the use of SCOFs have been reported. No previously published study reported SCOFs were used to reduce both prescribing errors and anti-emetic cost. This study attempts to measure these outcomes in a haematology-oncology pharmacy service. METHODS: The study consisted of a four-month control period, followed by a four-month test period following dissemination of the standardized order forms. In each period, prescriber errors and anti-emetic use were monitored. During the control period, using clinical studies from the primary literature and anti-emetic guidelines, 64 SCOFs representing the most commonly used chemotherapy regimens in the medical oncology and gynaecology oncology services were developed by the haematology-oncology pharmacy. Differences in prescribing error rate and anti-emetic cost were compared between each period and with the institution's historic prescribing error rate. RESULTS: During the control period, 1078 orders for oral and parenteral granisetron and ondansetron with combined total acquisition cost of $76 454.64 and a mean cost of $70.92 were dispensed. During the test period, the pharmacy dispensed 1121 orders with an acquisition cost of $73 331.61 and a mean cost of $65.42. A savings of $3123.03 resulted from a reduction of the amount prescribed in the test period. The difference in mean cost per order between the two periods was significant (P <0.037). Fifty-three prescribing errors out of 3592 medication orders were detected in the control period, while 12 errors out of 3585 medication orders were detected during the test period. A significant difference(P <0.0001) was detected between the two periods. There was a significant difference (P <0.0001) between the control period and the institution's historic prescribing error rate and no difference between the test period and the institution's historic prescribing error rate. CONCLUSION: SCOFs significantly reduced serotonin antagonist anti-emetic cost and prescribing error rate over a four-month period.

Antiemetics↗

An appraisal of chemical aversion (emetic therapy) approaches to alcoholism treatment.

More than 35,000 alcoholics have received chemical aversion (emetic therapy) in at least 75 settings worldwide since the 1930s. This consummatory aversion (CA) treatment, which pairs ethanol ingestion with emetically induced nausea, incorporates the highly efficient variety of learning known as taste aversion (TA) conditioning. The CA literature indicates that emetic therapy should induce conditioned alcohol aversions in many alcoholics. Such aversions have been widely reported by clinicians and have been confirmed by recent psychophysiological evidence. Long standing evidence of treatment effectiveness is found in the results of private hospitals which have consistently produced 1-yr abstinence rates approximating 60%. Diminished alcohol craving is a frequently reported benefit. Few experimental evaluations have been completed, as is generally the case for all alcoholism treatments, but those which used methodologically sound temporal parameters during conditioning have supported the clinical efficacy of emetic therapy. The clear need for more definitive research notwithstanding, there are compelling indications that emetic therapy is a useful component of multimodal treatment within certain alcoholic populations. However, its availability is severely limited. Many alcoholics could probably benefit from expanded treatment availability. The time is ripe for a reevaluation of resistances to the clinical use of emetic therapy alcoholism treatment.

Alcoholism↗

The broad-spectrum anti-emetic activity of the novel non-peptide tachykinin NK1 receptor antagonist GR203040.

1. Following our earlier observations that the tachykinin NK1 receptor antagonist CP-99,994 is an effective anti-emetic in ferrets, we have examined the anti-emetic effects of a more potent and novel NK1 receptor antagonist, GR203040, against various emetic stimuli in the ferret, dog and house musk shrew (Suncus murinus). 2. In ferrets, GR203040 (0.1 mg kg-1 s.c. or i.v.) is effective against emesis induced by radiation, cisplatin, cyclophosphamide, copper sulphate, ipecacuanha or morphine. 3. In animals in which emesis had been established with cisplatin, GR203040 (1 mg kg-1 s.c.) was fully effective as an interventional treatment. No further emesis was seen in animals treated with GR203040 whilst saline-treated animals continued to vomit. 4. GR203040 (0.1 mg kg-1 s.c.) retains anti-emetic efficacy in the ferret, even when given as a 6 h pretreatment, indicating that this compound has a long duration of action. The compound is also effective orally at the same dose, when given as a 90 min pretreatment. 5. GR203040 (0.1 mg kg-1 i.v.) is fully effective against ipecacuanha-induced emesis in the dog. 6. GR203040 is effective against motion- and cisplatin-induced emesis in Suncus murinus. These effects were seen at doses an order of magnitude greater than those shown to be effective against cisplatin in the ferret. 7. In conclusion, GR203040 is a novel anti-emetic agent, and the broad spectrum of anti-emetic activity, together with activity observed in three species, suggests that this compound is worthy of clinical investigation.

Animals↗

Evidence for non-ribosomal peptide synthetase production of cereulide (the emetic toxin) in Bacillus cereus.

Little is known about the process whereby the emetic toxin (or cereulide) of Bacillus cereus is produced. Two cereulide-producing strains of B. cereus were cloned and sequenced following polymerase chain reaction (PCR) amplification with primers that were specific for conserved regions of non-ribosomal peptide synthetase (NRPS) genes. The cloned regions of the B. cereus strains were highly homologous to conserved regions of other peptide synthetase nucleotide sequences. Primers were designed for two variable regions of the NRPS gene sequence to ensure specificity for the emetic strains. A total of 86 B. cereus strains of known emetic or non-emetic activity were screened using these primers. All of the emetic strains (n=30) displayed a 188 bp band following amplification and gel electrophoresis. We have developed an improved method of identifying emetic strains of B. cereus and provided evidence that cereulide is produced by peptide synthetases.

Amino Acid Motifs↗

Production of Bacillus cereus emetic toxin (cereulide) in various foods.

To determine the role of Bacillus cereus as a potential pathogen in food poisoning, the production of an emetic toxin (cereulide) by B. cereus was quantified in various food sources. The amount of emetic toxin in 13 of 14 food samples implicated in vomiting-type food poisoning cases ranged from 0.01 to 1.28 microg/g. A vomiting-type strain, B. cereus NC7401, was inoculated into various foods and incubated for 24 h at 20, 30, and 35 degrees C. In boiled rice, B. cereus rapidly increased to 10(7)-10(8) cfu/g and produced emetic toxin at both 30 and 35 degrees C. In farinaceous foods, the production of emetic toxin was as high as that in the food samples implicated in food poisoning. Low levels of emetic toxin were detectable in egg and meat and their products and a small quantity of toxin was detectable in liquid foods such as milk and soymilk when not aerated. Bacterial growth and toxin production was inhibited in foods cooked with vinegar, mayonnaise, and catsup, supposedly by the decreased pH of acetic acid. This is the first report that has quantified emetic toxin of B. cereus in various foods.

Bacillus cereus↗

A comparison of the efficacy of cyclizine and perhenazine in reducing the emetic effects of morphine and pethidine.

1 The ability of cyclizine (50 mg) and perphenazine (2.5 and 5.0 mg) to counteract the emetic effects of pethidine (100 mg) and morphine (10 and 15 mg) was compared in women undergoing a standard minor operation with a standard anaesthetic. 2 Perphenazine (5.0 mg) was as effective an anti-emetic as cyclizine (50 mg) and both were more effective than perphenazine (2.5 mg). 3 The reduction in vomiting and nausea by cyclizine (50 mg) and perphenazine (5 mg) was approximately the same following pethidine (100 mg) and morphine (10 mg) but much less against the larger dose of morphine. 4 Both anti-emetics had a rapid onset of action but their anti-emetic activity did not last as long as the emetic effect of morphine. 5 Perphenazine (5 mg) was accompanied by an unacceptably high incidence of restlessness. 6 In clinical practice cyclizine (50 mg) is preferred to perphenazine (5 mg) as an anti-emetic.

Antiemetics↗

A novel sensitive bioassay for detection of Bacillus cereus emetic toxin and related depsipeptide ionophores.

Of the toxins produced by Bacillus cereus, the emetic toxin is likely the most dangerous but, due to the lack of a suitable assay, the least well known. In this paper, a new, sensitive, inexpensive, and rapid bioassay for detection of the emetic toxin of B. cereus is described. The assay is based on the loss of motility of boar spermatozoa upon 24 h of exposure to extracts of emetic B. cereus strains or contaminated food. The paralyzed spermatozoa exhibited swollen mitochondria, but no depletion of cellular ATP or damage to plasma membrane integrity was observed. Analysis of the purified toxin by electrospray tandem mass spectrometry showed that it was a dodecadepsipeptide with a mass fragmentation pattern similar to that described for cereulide. The 50% effective concentration of the purified toxin to boar spermatozoa was 0.5 ng of purified toxin ml of extended boar semen-1. This amount corresponds to 10(4) to 10(5) CFU of B. cereus cells. No toxicity was detected for 27 other B. cereus strains up to 10(8) CFU ml-1. The detection limit for food was 3 g of rice containing 10(6) to 10(7) CFU of emetic B. cereus per gram. Effects similar to those provoked by emetic B. cereus toxin were also induced in boar spermatozoa by valinomycin and gramicidin at 2 and 3 ng ml of extended boar semen-1, respectively. The symptoms provoked by the toxin in spermatozoa indicated that B. cereus emetic toxin was acting as a membrane channel-forming ionophore, damaging mitochondria and blocking the oxidative phosphorylation required for the motility of boar spermatozoa.

Amino Acid Sequence↗

A PCR assay based on a sequence-characterized amplified region marker for detection of emetic Bacillus cereus.

A PCR assay for the detection of Bacillus cereus strains able to produce an emetic toxin (cereulide) was developed in this study based on a sequence-characterized amplified region (SCAR) derived from a random amplified polymorphic DNA (RAPD) fragment. One of the RAPD fragments generated was selected, cloned, and sequenced. A set of PCR primers was newly designed from the SCAR obtained (the sequence of the cloned RAPD fragment) and used in this assay. To determine the specificity of the assay, 30 different B. cereus strains, 8 other Bacillus strains (of six species), and 16 other non-Bacillus strains (from 16 genera) were tested. Results were positive for every emetic B. cereus strain and for only one nonemetic B. cereus strain. For all other bacterial strains, results were negative. Bacterial DNA for PCR was prepared by a simple procedure using Chelex 100 resin from the bacterial colony on the agar plate or from culture after growth in brain heart infusion medium. This PCR assay enabled us to detect the bacteria of emetic B. cereus grown on agar plates but not the bacteria of nonemetic B. cereus. To test this PCR assay for the monitoring of the emetic bacteria, 10 to 70 CFU of B. cereus DSM 4312 (emetic) per g of food was inoculated into several foods as an indicator, followed by a 7-h enrichment culture step. Because this PCR assay based on the SCAR derived from the RAPD fragment was able to detect bacterial cells, this assay should be useful for rapid and specific detection of emetic B. cereus.

Bacillus cereus↗

[Anti-emetic effect and safety of single dose of ondansetron injection in double-blind comparison study with placebo].

In order to make an objective evaluation of anti-emetic effect, safety and usefulness of ondansetron injection in nausea and vomiting associated with cancer chemotherapy, we carried out a double-blind placebo controlled comparative study in patients receiving high-single dose (50 mg/m2 or more) of cisplatin. Either 4 mg of ondansetron or saline injection was given intravenously at 15 min. before administration of cisplatin. If anti-emetic effect of the test drug was insufficient, an additional dose of 4mg of ondansetron was given intravenously, as the rescue medication. Ondansetron was significantly superior to placebo in anti-emetic effect (p < 0.001). Efficacy rates were 66.7% (22/33 cases) in ondansetron and 20.0% (6/30 cases) in placebo groups. Seven and 21 cases required rescue medication with 4 mg single intravenous dose of ondansetron due to insufficiency of anti-emetic effect, in ondansetron group and placebo group, respectively. Thus the number of patients who required rescue medication was obviously greater in placebo group than that in ondansetron group. The rates of inhibitory effect of rescue medication on nausea and emesis were 14.3% (1/7 cases) in ondansetron group and 61.9% (13/21 cases) in placebo group. Side effects were observed in 1 case (eruption) in ondansetron group and in 2 cases (headache, diarrhoea; 1 case each) in placebo group. Furthermore, fever developed in 1 case in placebo group after the rescue medication. Elevation of total bilirubin value was observed in 2 cases in ondansetron group and 1 case in placebo group, however, these changes were mild and did not pose noteworthy clinical problem. From these results, ondansetron was shown to possess an excellent anti-emetic effect on nausea and emesis induced by highly emetogenic anti-cancer drugs, such as cisplatin, and to have no problem in safety, and thus it was considered to be a useful anti-emetic agent.

Adult↗

Methodology and assessment in clinical anti-emetic research: a meta-analysis of outcome parameters.

There have been major clinical advances in the control of chemotherapy-induced nausea and emesis. These advances were achieved partly by the introduction of new anti-emetic agents but important improvement came from the use of existing agents in ways developed from the results of studies based on new approaches and methods in anti-emetic research. By developing basic research tools, improving methodology and applying psychometrically sound assessments better management or chemotherapy-induced nausea and vomiting has been achieved. The goals of anti-emetic assessment are discussed here along with data and examples of assessment techniques for emesis and nausea. Examination of 153 separate anti-emetic studies between the years of 1975 and 1988 showed that emesis was the most common outcome measure used and that approximately 1 out of five studies measured some other type of outcome usually in the context of nausea and emesis. The frequency of outcome events was most commonly the dimension assessed. Examination of size of the effect of an anti-emetic regimen for these anti-emetic studies showed it to be independent of the type of outcome measured, but to be quite dependent on how the outcome was quantified. For instance, differences in the frequency or incidence of either nausea or emesis were generally larger than measurements made of the duration of either of these.

Antiemetics↗

Emetic and antiemetic effects of opioids in the dog.

The emetic and antiemetic effects of opioid agonists were studied in awake dogs. The mu-agonists morphine, fentanyl and methadone, in sedative doses, prevented the emetic response to apomorphine and copper sulphate; only morphine induced emesis, at doses lower than those required to prevent emesis. The delta-agonist [D-Ala2,Met5]enkephalinamide (DALA) and [Leu5]enkephalin induced emesis in some of the dogs studied but had no antiemetic activity. The kappa-agonists bremazocine and ethylketocyclazocine (EKC) did not induce emesis but, at sedative doses, prevented the emetic response to apomorphine. The emetic effect of DALA was antagonized by naloxone in some dogs; the antiemetic effect of morphine, bremazocine and EKC was blocked by both naloxone and MR 2266. The non-opioid sedatives diazepam, phenobarbital and xylazine, administered in sedative doses, did not prevent apomorphine-induced emesis. Our results suggest that a delta-receptor is involved in the emetic effect and a mu- and/or or kappa-receptor in the antiemetic effect of opioids.

Animals↗