Serotoninergic System Research Articles

Phytotherapy of experimental depression: Kalanchoe integra Var. Crenata (Andr.) Cuf Leaf Extract.

Context:Kalanchoe sp. have been used since 1921 for central nervous system (CNS) disorders such as psychosis and depression. It is known to possess CNS depressant effects.Aims:To investigate the antidepressant properties of the aqueous leaf extract of Kalanchoe integra.Settings and Design:The study was carried out at the Kwame Nkrumah University of Science and Technology between 6 a.m. and 3 p.m.Materials and Methods:ICR mice were subjected to the forced swimming test (FST) and tail suspension test (TST) after they had received extract (30-300 mg/kg), fluoxetine (3-30 mg/kg), desipramine (3-30 mg/kg) orally, or water (as vehicle). In a separate experiment, mice were pre-treated with reserpine (1 mg/kg), α-methyl paratyrosine (AMPT; 400 mg/kg), both reserpine (1 mg/kg) and AMPT (200 mg/kg) concomitantly, or p-chlorophenylalanine (pCPA; 200 mg/kg) to ascertain the role of the noradrenergic and serotoninergic systems in the mode of action of the extract.Statistical analysis used:Means were analyzed by analysis of variance (ANOVA) followed by Newman-Keuls’ post hoc test. P < 0.05 was considered significant.Results:In both FST and TST, the extract induced a decline in immobility, indicative of antidepressant-like effect. This diminution in immobility was reversed by pCPA, but not by reserpine and/or AMPT. The extract increased the swimming and climbing scores in the FST, suggestive of possible interaction with serotoninergic and noradrenergic systems. In the TST, the extract produced increases in both curling and swinging scores, suggestive of opioidergic monoaminergic activity, respectively.Conclusions:The present study has demonstrated the antidepressant potential of the aqueous leaf extract of K. integra is mediated possibly by a complex interplay between serotoninergic, opioidergic, and noradrenergic systems.

Impairment in Pain Perception in Adult Rats Lesioned as Neonates with 5.7-Dihydroxytryptamine.

Whereas some studies have demonstrated the essential role of 5-hydroxytryptamine (5-HT) in tramadol and acetaminophen analgesia, other research has presented conflicting results. To dispel doubts, some aspects of the involvement of 5-HT in the antinociceptive properties of these drugs remain to be clarified. The aim of this study was to determine whether the serotoninergic system dysfunction produced by neonatal 5-HT lesion in rats may affect the antinociceptive effects of tramadol and acetaminophen administered in adulthood. Three days after birth, the control rats were pretreated with desipramine HCl (20 mg/kg i.p.) 30 min before intraventricular saline--vehicle injection. A separate group received 5.7-DHT; 2×35 µg in each lateral ventricle. At the age of 8 weeks, 5-HT and 5-hydroxyidoleaceticacid (5-HIAA) concentrations were determined in the thalamus and spinal cord by an HPLC/ED method. The antinociceptive effects of tramadol (20 mg/kg i.p.) or acetaminophen (100 mg/kg i.p.) were evaluated by a battery of tests. 5.7-DHT lesioning was associated with a reduction in 5-HT and 5-HIAA content of the thalamus (>85% and >90%) and spinal cord (>58% and 70%). Neonatal 5.7-DHT treatment produced a significant reduction in the antinociceptive effect of tramadol in the hot plate, tail-immersion, paw withdrawal and writhing tests. In the formalin hind paw test, the results were ambiguous. 5-HT lesion was also associated with a decrease in the analgesic effect of acetaminophen in the hot plate and writhing tests. A similar relationship wasn't found in the other assessments conducted with the use of acetaminophen. The present study provides evidence that (1) an intact serotoninergic system is required for the adequate antinociceptive action of tramadol, and (2) the serotoninergic system exerts a negligible influence on acetaminophen-induced analgesia in rats. We hypothesize that similar abnormalities in nociception may occur in patients with 5-HT dysfunction (e.g. depression), so these results should be complied in analgesic dosage adjustment.

Exploring the Frontiers of Serotoninomics in Male Reproduction: The Future Ahead

Since its discovery in the past century by Green, Page and Rapport (1948), to the present time, several physiological actions of serotonin has been discovered. Besides physiological functions, several components of serotoninergic system and its participation in some neurological diseases (i.e. depression, schizophrenia) also have been reported. During previous decades, a lot of experimental techniques have allowed us to locate, detect, analyze and describe the serotoninergic system and its role in different organs and tissues; at the time of 60’s and 70’s of century XX, techniques such as histochemistry for indolamines or Falck-Hillarp method, fluorescence microscopy and the realization of measurements of concentrations in tissues or blood using chromatography enabled significant progress in the study of this indolamine;

Antidepressant-Like Effect of the Leaves of Pseudospondias microcarpa in Mice: Evidence for the Involvement of the Serotoninergic System, NMDA Receptor Complex, and Nitric Oxide Pathway.

Depression continues to be a major global health problem. Although antidepressants are used for its treatment, efficacy is often inconsistent. Thus, the search for alternative therapeutic medicines for its treatment is still important. In this study, the antidepressant-like effect of Pseudospondias microcarpa extract (30–300 mg kg−1, p.o.) was investigated in two predictive models of depression—forced swimming test and tail suspension test in mice. Additionally, the mechanism(s) of action involved were assessed. Acute treatment with the extract dose dependently reduced immobility of mice in both models. The antidepressant-like effect of the extract (100 mg kg−1, p.o.) was blocked by p-chlorophenylalanine and cyproheptadine but not prazosin, propranolol, or yohimbine. Concomitant administration of d-cycloserine and the extract potentiated the anti-immobility effect. In contrast, d-serine, a full agonist of glycine/NMDA receptors, abolished the effects. Anti-immobility effects of PME were prevented by pretreatment of mice with L-arginine (750 mg kg−1, i.p.) and sildenafil (5 mg kg−1, i.p.). On the contrary, pretreatment of mice with L-NAME (30 mg kg−1, i.p.) or methylene blue (10 mg kg−1, i.p.) potentiated its effects. The extract produces an antidepressant-like effect in the FST and TST that is dependent on the serotoninergic system, NMDA receptor complex, and the nitric oxide pathway.

Brain neurotransmitter systems gene Polymorphism: the Search for pharmacogenetic markers of efficacy of haloperidol in Russians and Tatars

Antipsychotics are the main drugs for the treatment of severe mental illness--schizophrenia affects about 1% of the population. The mechanism of action of neuroleptics is still up to the end. Several studies in the field of pharmacogenetics confirm enourmous influence of several neurotransmitter systems in the brain on the efficiency and the development of side effects. In this paper, we analyzed the association of nine polymorphic variants of five genes of dopaminergic and serotonergic systems DRD4, HTR2A, TPH1, SLC18A1, COMT in Russian and Tatars patients living in the Republic of Bashkortostan (RB) with the efficiency of a typical antipsychotic haloperidol on the scale of positive and negative systems of PANSS. The study established pharmacogenetic markers of increased and decreased effectiveness of therapy with haloperidol in the treatment groups. The results of this study confirm the importance of changes in the nucleotide sequences of the studied genes of the serotoninergic and dopaminergic systems (HTR2A, TPH1, SLC18A1 COMT, DRD4) in the formation of individual sensitivity to haloperidol. The results of our work considered as preliminary contact, requires an increase in the number of samples studied.

Platelet activation and arterial peripheral serotonin turnover in cardiac remodeling associated to aortic stenosis

Peripheral serotonin (5-HT) has been involved in adverse cardiac remodeling and valve fibrosis. The peripheral levels of 5-HT mainly depend on its release from activated platelets and degradation by monoamine oxidase A (MAO-A). The SERAOPI study investigated the relationship between arterial serotoninergic system, degree of platelet activation and cardiac remodeling, in patients with aortic valve stenosis (AS). Thirty patients with severe AS and 15 control subjects underwent transthoracic echocardiography, radial, and aortic arterial blood sampling. Measurements of 5-HT and its MAO-A-dependent degradation product, 5-HIAA, were performed by HPLC. Arterial platelet activation was assessed by flow cytometry analysis of platelet surface expression of P-selectin and activated integrin GPIIb/IIIa. Activated platelets and arterial plasma 5-HT increased in AS patients as compared to control subjects (P-selectin 1.08 ± 0.2MFI vs. 0.49 ± 0.1MFI, P = 0.04; GPIIb/IIIa 0.71 ± 0.1MFI vs. 0.35 ± 0.1MFI; P = 0.0015 and arterial plasma 5-HT 11.55 ± 1.6 nM vs. 6.18 ± 0.7 nM, P = 0.028, respectively). Moreover, 5-HT was strongly correlated to left ventricular hypertrophy assessed by echocardiography. The correlation was independent of cardiovascular risk comorbidities and others echocardiographic AS parameters. Finally, plasma 5-HIAA increased in AS patients (74.64 ± 9.7 nM vs. 37.16 ± 4.1 nM; P = 0.0002) indicating a higher 5-HT degradation rate by MAO-A. Platelet activation, arterial circulating serotonin, and serotonin degradation increased in patients with AS. These observations suggest that the serotoninergic system may contribute to the pathogenesis of AS including valve fibrosis and adverse ventricular remodeling.

Association of serotonin transporter gene (5HTT) polymorphism and juvenile myoclonic epilepsy: a case-control study.

Serotonin levels might alter susceptibility to seizures. Serotonin transporter (5HTT) gene polymorphisms were found to be associated with some forms of epilepsy. Here, we attempted to examine an association between 5HTT VNTR allele variants in a serotonin transporter gene and epileptogenesis in juvenile myoclonic epilepsy (JME) cases. We conducted a case-control candidate gene study evaluating the frequencies of 5HTT VNTR allele variants using SYBR green real-time PCR with melting curve analysis in JME patients and healthy subjects. Forty patients with JME were selected from the Epilepsy Outpatient Clinic of Kasr Al Ainy Hospital, Cairo University, who had been classified according to the electroclinical classification of the ILAE. The control group consisted of 40 healthy Egyptian subjects. The less efficient transcriptional genotypes for 5-HTT polymorphisms were more frequent in JME patients (OR 9.33, CI 2.85-30.60; p value < 0.001). In our study we detected an association between the presence of 5-HTTVNTR with less transcriptional efficient genotypes and JME, which suggests that modulation of the serotoninergic system might be indicated in epileptogenesis in JME.

Pharmacological strategies for the management of levodopa-induced dyskinesia in patients with Parkinson's disease.

L-Dopa-induced dyskinesias (LID) are the most common adverse effects of long-term dopaminergic therapy in Parkinson's disease (PD). However, the exact mechanisms underlying dyskinesia are still unclear. For a long time, nigrostriatal degeneration and pulsatile stimulation of striatal postsynaptic receptors have been highlighted as the key factors for the development of LID. In recent years, PD models have revealed a wide range of non-dopaminergic neurotransmitter systems involved in pre- and postsynaptic changes and thereby contributing to the pathophysiology of LID. In the current review, we focus on therapeutic LID targets, mainly based on agents acting on dopaminergic, glutamatergic, serotoninergic, adrenergic, and cholinergic systems. Despite a large number of clinical trials, currently only amantadine and, to a lesser extent, clozapine are being used as effective strategies in the treatment of LID in clinical settings. Thus, in the second part of the article, we review the placebo-controlled trials on LID treatment in order to disentangle the changing scenario of drug development. Promising results include the extension of L-dopa action without inducing LID of the novel monoamine oxidase B- and glutamate-release inhibitor safinamide; however, this had no obvious effect on existing LID. Others, like the metabotropic glutamate-receptor antagonist AFQ056, showed promising results in some of the studies; however, confirmation is still lacking. Thus, to date, strategies of continuous dopaminergic stimulation seem the most promising to prevent or ameliorate LID. The success of future therapeutic strategies once moderate to severe LID occur will depend on the translation from preclinical experimental models into clinical practice in a bidirectional process.

Genetic variations in the serotoninergic system and environmental factors contribute to aggressive behavior in Chinese adolescents

Aggressive behavior is a major public health problem worldwide and has been associated with many gene variants, especially those related to the serotonin (5-hydroxytryptamine, 5-HT) system, and environmental factors. However, the overall contribution of serotonin-related genes to aggressive behavior is not well understood. With a sample of 478 healthy Chinese volunteers, this study investigated the relation between aggressive behavior and genetic variations of the serotoninergic system (as characterized by 129 representative polymorphisms) interacting with environmental factors (parental warmth and acceptance; stressful life events). We adopted a system-level approach to identify SNPs and environmental factors associated with aggressive behavior, and estimated their overall contribution to aggressive behavior using multiple regression, which was then verified by permutation analysis. We identified 12 SNPs that made statistically significant contributions to aggressive behavior. Next, main effects, interactions among these SNPs, and interactions between these SNPs and environmental factors were assessed using multiple regression. The final model accounted for approximately 19% of the variance for aggressive behavior. Permutation analysis confirmed that the probability of obtaining these findings by chance was low (p=0.045, permuted for 1000 times). These results showed that genetic variations in the serotoninergic system, combined with environmental risk factors, made a moderate contribution to individual differences in aggressive behavior among a healthy population sample.

Serotonin antagonists induce anxiolytic and anxiogenic-like behavior in zebrafish in a receptor-subtype dependent manner

Motor function and anxiety-like responses are easily quantifiable in zebrafish, a novel model organism for behavioral pharmacology. Activation of serotonin receptors through the use of selective agonists has been shown to alter anxiety-like behaviors in zebrafish. However, few studies have examined the effect of blockade of specific serotonin receptors. In the current study, we examine the effect of 4 serotonin receptor antagonists selective for 5-HT1A, 5-HT1B/D, 5-HT2, and 5-HT3 receptors on zebrafish motor and anxiety-like responses. Exposure to the receptor antagonists did not change baseline motor responses. However, when placed in a novel environment, zebrafish previously exposed to GR 55562 (5-HT1B/D antagonist) exhibited reduced anxiety-like behavior, whereas zebrafish previously exposed to p-MPPF (5-HT1A antagonist), Ketanserin (5-HT2 antagonist), or Ondasetron (5-HT3 antagonist) exhibited increased anxiety-like behaviors. These results show that drugs developed for mammalian serotonin receptors are efficacious in the zebrafish too, a finding that demonstrates evolutionary conservation of the serotoninergic system. The results also imply that zebrafish may be an appropriate animal model for examining the serotonergic neurotransmitter system in vertebrates.

El papel del gen del transportador de serotonina en los trastornos de la conducta alimentaria

BackgroundThe serotoninergic system has been implicated in mood and appetite regulation, and the serotonin transporter gene (SLC6A4) is a commonly studied candidate gene for eating disorders. However, most studies have focused on a single polymorphism (5-HTTLPR) in SLC6A4. ObjectiveWe present the studies published on the association between eating disorders (ED) and 5-HTTLPR polymorphism in anorexia nervosa (AN), bulimia nervosa (BN), and eating disorders not otherwise specified (EDNOS). MethodSearch of databases: MEDLINE, ISI, and PubMed for SLC6A4 and ED. ConclusionsFrom a review of 37 original articles, it was suggested that carriers of S allele is a risk factor for eating disorders, especially for AN. However, BN did not show any association. Also, BMI, impulsivity, anxiety, depression, and age of onset have been associated with S allele in ED patients.

Further definition on the multiple partner choice arena: a potential animal model for the study of premature ejaculation.

The multiple partner choice arena (MPCA) is an experimental setup in which male rats display a significant shortening of ejaculation latency, which is the main characteristic of premature ejaculation (PE) in men. Thus, the MPCA is a potential animal model for PE. In this study, we further analyze whether the features of the MPCA satisfy the validity criteria for it to be considered an animal model as well as the possible participation of the serotoninergic system in the faster ejaculation exhibited by male rats in the MPCA. In Experiment 1, male rats were tested in a standard arena to assess their sexual behavior, then were assessed 1 week later in the MPCA. Another group was first tested in the MPCA, then in a standard arena. In Experiment 2, male rats divided into two groups were treated daily with WAY-100635 (5-HT(1A) antagonist) or vehicle for 15 days. In each group, half of the subjects were tested in a standard arena and half were tested in the MPCA on days 1, 8, and 15 of treatment. Number of intromissions and intromission and ejaculation latencies were the main outcome measures. In Experiment 1, males tested in the MPCA ejaculated significantly faster, regardless of the order in which they were evaluated in both arenas. In Experiment 2, the administration of WAY-100635 increased intromission and ejaculation latencies, and the number of intromissions in the MPCA. The results obtained in the MPCA support its use as an animal model for PE evaluation.

Effects of Neurotensin on the Effects of Pain Stress in Rats with Neurotoxic Lesions to Serotoninergic Structures of the Substantia Nigra of the Brain

The aim of the present work was to study the effects of neurotensin on the behavior of rats with neurotoxic lesions to the serotoninergic structures of the substantia nigra of the brain. Changes in the reproduction of conditioned passive avoidance reactions were analyzed, as were changes in the effects of pain stimulation on the activity of rats in the open field. Administration of 5,7-dihydroxytryptamine into the substantia nigra was found to impair the reproduction of passive avoidance reactions and to weaken the suppressive effects of pain stimulation. Administration of the serotonin 5-HT1A receptor antagonist p-MPPF into the substantia nigra had similar effects on the effects of pain stimulation. Administration of neurotensin into the caudate nucleus before application of pain stimulation prevented the toxin-induced impairment to defensive behavior and its effects on motor activity. Administration of neurotensin into the substantia nigra 24 h after pain stimulation had no marked effect on the passive avoidance reaction but increased motor activity during its reproduction. The effects of giving neurotoxin into the substantia nigra were linked with weakening of the action of pain stress on motor activity. Prevention of the development of this effect in rats after microinjection of neurotensin into the caudate nucleus may be due to recovery of neurotoxin-impaired reproduction of passive avoidance and can be explained by normalization of the balance of interactions between the serotoninergic (5-HT) and dopaminergic systems of the brain.

Structural Changes in the Subnuclei of the Parabrachial Complex in Rats with Serotoninergic System Deficiency during Prenatal Development

Experiments were performed on the offspring of female Wistar rats (n = 8) given parachlorophenylalanine on day 16 of pregnancy to decrease endogenous serotonin levels in the offspring. Histological, immunocytochemical, and morphometric methods were used in rat pups on days 10 and 14 of postnatal development (5–6 individuals at each time point) for studies of the dorsal and ventral subnuclei of the lateral part of the parabrachial complex. The results showed that serotonin deficiency led to changes in the structure of these subnuclei. The population of large, multipolar neurons in the ventral subnucleus was found to be more sensitive to decreased serotonin levels. Experimental animals showed decreases in the body sizes of these neurons by a factor of 1.6 compared with controls, with virtually no change in the number of cells in this population. The morphological characteristics of small neurons corresponded to those in controls, though there was a reduction in the number of cells, which may explain the rarefaction of neurons in this nucleus. In the dorsal subnucleus of experimental animals, neurons of both of the populations in this structure underwent more marked changes. The sizes of both large and smaller neuron cell bodies decreased significantly, by factors of 2.0 and 1.8 respectively; the cytoplasmic volumes of these cells decreased compared with controls; the numbers of cells in both populations remained largely unaltered. Reactions detecting glial fibrillary acidic protein showed increases in the numbers of the astrocyte glial population in the early postnatal period in the experimental animals.

Morphofunctional Studies of the Involvement of the Serotoninergic System in the Control of Postural and Locomotor Functions

Various transmitter systems, including the serotoninergic, influence the locomotor behavior of animals. Studies have shown that the spinal cord, deprived of supraspinal control, has mechanisms able to induce locomotor activity in the hindlimbs and that the afferent system can trigger these mechanisms. Behavioral experiments on rats with complete transection of the spinal cord showed that pharmacological suppression of the serotoninergic system leads to suppression of motor activity associated with activation of support reactions (locomotor training). Histological studies did not identify any effect of activating support reactions on neuron survival or the distribution of synaptic contacts in spinal cord segments L2–L4. However, suppression of the serotoninergic system has been shown to lead to changes in cells in laminae 1–3 of the dorsal horns and in Rexed lamina 7, along with redistribution of synaptic contacts in Rexed laminae 1–4 in the dorsal horns of the spinal cord.

Antinociceptive Properties of Ascorbic Acid: Evidence for the Mechanism of Action

Background: Ascorbic acid is amongst important water-soluble vitamins and when used orally in high-doses it has been observed to relieve pain and reduce opioid use in patients. However no controlled trial has compared the antinociceptive effects of ascorbic acid with other analgesic groups on animal models, and investigated the involved mechanisms. Objectives: In the present study, the antinociceptive effect of vitamin C on male mice was investigated and compared with morphine and diclofenac. Also, possible mechanisms were assayed. Materials and Methods: Male albino mice were used in this study. Antinociception was measured using the writhing test, tail flick and formalin tests. Ascorbic acid was used in three doses (30, 150 and 300 mg/kg, IP) and compared with the antinociceptive effects of 10 mg/kg of morphine as an opioid analgesic agent and 5-10 mg/kg of diclofenac as a nonsteroidal anti-inflammatory drug (NSAID) analgesic agent. The antinociceptive effect of ascorbic acid (300 mg/kg) was compared before and after treatment with naloxone (4 mg/kg), ondansetron (0.5 mg/kg), atropine (5 mg/kg) and metoclopramide (1 mg/kg) in the writhing test. Results: Vitamin C caused dose-dependent antinociceptive effects in acetic acid writhing test (P < 0.05). It had no significant effect in the tail flick test. Meanwhile, vitamin C in high doses reduced pain in the second phase of the formalin test (P < 0.05). Morphine had higher nociceptive effects in comparison to ascorbic acid in the writhing test (P < 0.05). In the second phase of the formalin test the antinociceptive effects of vitamin C (300 mg/kg) was not significantly different with morphine at dose of 10 mg/kg. There was not significant difference between vitamin C (300 mg/kg) and diclofenac (10 mg/kg) in the second phase of the formalin test. Metoclopramide and ondansetrone reduced the antinociceptive effects of vitamin C. Conclusions: The results obtained from the acetic acid induced writhing test and second phase of the formalin test indicate that vitamin C possess antinociceptive activity especially on inflammatory pain. Ondansetrone and metoclopramide reduced the effects of ascorbic acid, which may be because ascorbic acid produced antinociception through mechanisms that may be involved in dopaminergic and serotoninergic systems.

EHMTI-0189. Tryptophan-kynurenine metabolism in migraine patients

Alterations of the serotoninergic system are well-known in migraine, however, the other main route of tryptophan metabolism, the kynurenine pathway has not yet been investigated in migraine. Psychiatric comorbidity, especially depression is highly frequent in migraine patients, but the exact pathomechanism is not fully clarified.

Effects of Neonatal Fluvoxamine Administration on the Physical Development and Activity of the Serotoninergic System in White Rats

Selective serotonin reuptake inhibitors (SSRIs), including fluvoxamine, are widely used to treat depressive disorders in pregnant women. These antidepressants effectively penetrate through the placental barrier, affecting the fetus during the critical phase of neurodevelopment. Some clinical studies have linked prenatal exposure to SSRIs with increased neonatal mortality, premature birth, decreased fetal growth and delay in psychomotor development. However, the effects of prenatal exposure to SSRIs remain unknown. The administration of SSRIs in rodents during the first postnatal weeks is considered as an model for studying the effects of prenatal SSRIs exposure in human. The aim of this work was to study the acute effects of chronic fluvoxamine (FA) administration in white rat pups. The study was carried out in male and female rat pups treated with FA (10 mg/kg/day, intraperitoneally) from postnatal days 1 to 14. The lethality level, body weight, age of eye opening, and motor reflex maturation were recorded. The contents of biogenic amines and their metabolites in different brain structures were also determined. It was shown that neonatal FA administration led to increased lethality level, reduced body weight, and delayed maturation of motor reflexes. Furthermore, increased noradrenalin level in hypothalamus, serotonin level in hippocampus and serotonin metabolite 5-HIAA level in frontal cortex, hypothalamus, hippocampus, and striatum were observed in drug-treated animals compared to the control group. We can conclude that the altered activity of the serotoninergic system induced by fluvoxamine administration at early developmental stages leads to a delay in physical and motor development.

Levodopa-Dependent Movement Disorder and Oligoastrocytoma Double Trouble or Dependent from Each Other?

Background: Inborn errors of neurotransmission and decreased function of the dopaminergic and serotoninergic systems could often lead to movement disturbances and impaired development.

Analgesic interaction between ondansetron and acetaminophen after tonsillectomy in children: the Paratron randomized, controlled trial.

The mechanism of action of acetaminophen remains unclear. One hypothesis involves an interaction with the serotoninergic system. Antagonists to serotonin (5-HT)3 receptors (setrons) have antiemetic properties. Therefore, co-administration of acetaminophen and a setron could lead to a decrease or a loss of acetaminophen analgesic effects. The aim of this study was to demonstrate such an interaction. Paratron is a prospective, randomized, controlled, double-blind, parallel group trial. All children aged 2-7 years (n = 69) scheduled for a tonsillectomy ± adenoidectomy received intraoperative acetaminophen with ondansetron or droperidol. Pain scores [Children's Hospital of Eastern Ontario Pain Scale (CHEOPS)], morphine consumption and the incidence of post-operative nausea and vomiting (PONV) were measured for 24 h following surgery. Pain scores were not different at all times between the groups but median morphine consumption (μg) in recovery was 322.5 [interquartile range (IQR) 0.0-500.0] and 0 (IQR 0-0) in the ondansetron (n = 35) and droperidol (n = 34) groups, respectively (p = 0.004). The percentages of patients who received morphine titration were 57.1% and 20.6% in the ondansetron and droperidol groups, respectively (p = 0.008). No significant difference was found for PONV. An interaction between acetaminophen and ondansetron is suggested, with children receiving three times more morphine during pain titration in the recovery room. More studies are necessary to evaluate whether this finding is clinically relevant enough to preclude the simultaneous perioperative administration of both drugs in the future.