Ondansetron reducing pain on injection of etomidate: a controlled randomized study / Ondansetrona reduz a dor da injeção de etomidato: estudo randômico controlado / El ondansetrón reduce el dolor de la inyección de etomidato: estudio aleatorizado controlado

Introduction: Etomidate causes pain when injected intravenously. In this study we sought to determine if pretreatment by ondansetron reduces the pain on injection of etomidate. Methods: In this randomized, double blinded, placebo-controlled clinical trial, 20 patients of both sexes aged between 18 and 50 years of American Society of Anesthesiologists (ASA) physical status class I or II, whom were candidates for various elective surgical procedures and need more than one intravenous access were enrolled in the study. On arrival to the operating room two 22 gauge cannulas were inserted into veins on the dorsum of both hands. Following the infusion of 100 mL normal saline into both intravenous lines, using an elastic band, venous drainage of hands was occluded at midarm. The patients were administered 8 mg (2 mL) of ondansetron into one hand and 2 mL of 0.9% saline into the other hand at the same time. The elastic band was removed after 1 min and 2 mg (1 mL) of etomidate was administered at the same rate simultaneously into intravenous lines. The patients were asked to give a score of pain based on a verbal analog scale (VAS) to each hand. Results: A total number of 20 patients were studied (male = 55%, female = 45%). The mean age of the participants was 37.5 ± 13.1 years old and the mean weight was 67.7 ± 7.3 kg. The mean VAS for injection pain of etomidate after pre-administration of intravenous ondansetron was 1.5 ± 1.2 which was lower compared to pre-administration of placebo (3.2 ± 2.8, p < 0.05). Conclusion: This study illustrates that pre-treatment with intravenous ondansetron significantly reduces the pain on injection of etomidate. .

Justificativa e objetivo: etomidato causa dor quando administrado por via intravenosa. Neste estudo buscamos determinar se o pré-tratamento com ondansetrona reduz a dor causada pela injeção de etomidato. Métodos: neste estudo clínico randômico, duplo-cego e controlado por placebo, 20 pacientes de ambos os sexos, entre 18 e 50 anos, estado físico ASA I ou II, candidatos a procedimentos cirúrgicos eletivos que exigiam mais de um acesso intravenoso, foram incluídos. Ao darem entrada na sala de cirurgia, duas cânulas de calibre 22 foram inseridas nas veias do dorso de ambas as mãos. Após a infusão de 100 mL de solução salina normal em ambas as linhas de acesso intravenoso, a drenagem venosa das mãos foi ocluída até o meio do braço com o uso de um torniquete elástico. Os pacientes receberam 8 mg (2 mL) de ondansetrona em uma das mãos e 2 mL de solução salina a 0,9% na outra mão ao mesmo tempo. O torniquete foi removido após um minuto e 2 mg (1 mL) de etomidato foram administrados na mesma proporção simultaneamente nas linhas intravenosas. Pediu-se aos pacientes que dessem pontos à dor em cada mão, com base em uma escala verbal analógica (EVA). Resultados: avaliamos 20 pacientes (homens = 55%, mulheres = 45%). A média de idade e de peso foi de 37,5 ± 13,1 anos e 67,7 ±7,3 kg. A média do escore EVA para dor causada pela injeção de etomidato após a pré-administração de ondansetron IV foi de 1,5 ± 1,2, que foi menor em comparação com a pré-administração de placebo (3,2 ± 2,8, p < 0,05). Conclusão: este estudo mostra que o pré-tratamento com ondansetrona IV reduz significativamente a dor causada pela injeção de etomidato. .

Introducción: el etomidato causa dolor cuando es administrado por vía intravenosa. En este estudio buscamos determinar si el pretratamiento con ondansetrón reduce el dolor causado por la inyección de etomidato. Métodos: fueron incluidos en este estudio clínico aleatorizado, doble ciego y controlado por placebo, 20 pacientes de ambos sexos con edades entre 18 y 50 años, estado físico ASA I o II, candidatos a varios procedimientos quirúrgicos electivos, que exigían más de un acceso intravenoso. Al entrar en quirófano, se insertaron dos cánulas de calibre 22 en las venas del dorso de ambas manos. Después de la infusión de 100 mL de solución salina normal en ambas líneas de acceso intravenoso; usando un torniquete elástico, el drenaje venoso de las manos se cerró hasta la mitad del brazo. Los pacientes recibieron 8 mg (2 mL) de ondansetrón en una de las manos y 2 mL de solución salina al 0,9% en la otra mano al mismo tiempo. El torniquete fue retirado después de 1 min y 2 mg (1 mL) de etomidato se administró en la misma proporción simultáneamente en las líneas intravenosas. Se les solicitó a los pacientes que hiciesen una puntuación del dolor en cada mano, basándose en una escala verbal analógica (EVA). Resultados: evaluamos a un total de 20 pacientes (un 55% hombres y un 45% mujeres). La media de edad y del peso de los participantes fue de 37,5 ± 13,1 años y de 67,7 ±7,3/kg, respectivamente. El promedio de la puntuación EVA para el dolor causado por la inyección de etomidato después de la preadministración de ondansetrón iv fue de 1,5 ± 1,2, siendo menor en comparación con la preadministración de placebo (3,2 ± 2,8; p < 0,05). Conclusión: este estudio demuestra que el pretratamiento con ondansetrón iv reduce ...

Antagonistas serotoninérgico e noradrenérgico por via subaracnoidea aumentam a resposta álgica em ratos / Subarachnoid serotonergic and noradrenergic antagonists increase the pain response in rats

JUSTIFICATIVA E OBJETIVOS: Há evidências de que a passagem de informações nociceptivas pelo corno posterior da medula espinhal (CPME) seguindo para níveis rostrais do sistema nervoso central sofre profundas influências excitatórias e inibitórias. A presente pesquisa teve como objetivo comparar os efeitos da metissergida, da fentolamina e da fentolamina associada à metissergida, administrados por via subaracnoidea, sobre as fases I, intermediária e II do teste da formalina modificado em ratos. MÉTODO: Foram utilizados 28 ratos Wistar machos, distribuídos aleatoriamente em quatro grupos (n = 7) para receber solução salina (GC), fentolamina (GF), metissergida (GM) ou fentolamina associada à metissergida (GFM) por via subaracnoidea. A dor foi induzida pela administração de formalina na região dorsal da pata posterior direita. O teste foi dividido em três fases; fase I, intermediária e fase II. A análise estatística dos resultados foi realizada utilizando o programa SPSS (Statistical Package for Social Sciences), adotando o nível de significância de 5 por cento. RESULTADOS: Na fase intermediária, o número de elevações da pata foi significativamente maior nos grupos GF, GM e GFM quando comparados com o grupo GC. CONCLUSÕES: Os resultados sugerem a existência de efeito noradrenérgico e serotoninérgico no sistema inibitório descendente da dor aguda, com a possibilidade de emprego de agonistas serotoninérgicos e α1-adrenérgicos para controle da dor aguda.

BACKGROUND AND OBJECTIVES: There is evidence that the passage of nociceptive information through the posterior horn of the spinal cord (PHSC) on its way to rostral levels of the central nervous system undergoes profound excitatory and inhibitory influences. The objective of the present study was to compare the effects of the subarachnoid administration of methysergide, phentolamine, and phentolamine associated with methysergide on phases I, intermediate, and II of the modified phormaline test in rats. METHODS: Twenty-eight male Wistar rats distributed randomly in four groups (n = 7) to received subarachnoid saline solution (GC), phentolamine (GF), methysergide (GM), or phentolamine associated with methysergide (GFM). Pain was induced by the administration of phormaline in the dorsal region of the right hind paw. The test was divided in three phases: phase I, intermediate, and phase II. Statistical analysis of the results was performed using the software SPSS (Statistical Package for Social Sciences), adopting a level of significance of 5 percent. RESULTS: In the intermediate phase the number of paw elevations was significantly higher in GF, GM, and GFM groups when compared to the GC group. CONCLUSIONS: The results suggest the existence of a noradrenergic and serotonergic effect in the inhibitory descending system of acute pain, with the possibility of using serotonergic and α1-adrenergic antagonists to control acute pain.

JUSTIFICATIVA Y OBJETIVOS: Existen evidencias de que el paso de informaciones nociceptivas por el cuerno posterior de la médula espinal (CPME), y que continúa hacia niveles rostrales del sistema nervioso central, sufre profundas influencias excitatorias e inhibitorias. La presente investigación quiso comparar los efectos de la metisergida, de la fentolamina y de la fentolamina asociada a la metisergida, administrados por vía subaracnoidea, sobre las fases I, intermedia y II del test de la formalina modificado en ratones. MÉTODO: Fueron utilizados en el experimento, 28 ratones Wistar machos, distribuidos aleatoriamente en cuatro grupos (n = 7), para recibir una solución salina (GC), fentolamina (GF), metisergida (GM) o fentolamina asociada a la metisergida ((GFM). El dolor fue inducido por la administración de formalina en la región dorsal de la pata posterior derecha. El test fue dividido en tres fases: fase I, intermedia y fase II. El análisis estadístico de los resultados fue hecho utilizando el programa SPSS (Statistical Package for Social Sciences), [Paquete Estadístico para las Ciencias Sociales], adoptando el nivel de significancia de un 5 por ciento. RESULTADOS: En la fase intermedia, el número de elevaciones de la pata fue significativamente mayor en los grupos GF, GM y GFM cuando se comparó con el grupo GC. CONCLUSIONES: Los resultados nos sugieren la existencia de un efecto noradrenérgico y serotoninérgico en el sistema inhibitorio descendiente del dolor agudo, con la posibilidad del uso de agonistas serotoninérgicos y α1-adrenérgicos para el control del dolor agudo.

Role of the serotoninergic system in the sodium appetite control

The present article reviews the role of the serotoninergic system in the regulation of the sodium appetite. Data from the peripheral and icv administration of serotoninergic (5-HTergic) agents showed the participation of 5-HT2/3 receptors in the modulation of sodium appetite. These observations were extended with the studies carried out after brain serotonin depletion, lesions of DRN and during blockade of 5-HT2A/2C receptors in lateral parabrachial nucleus (LPBN). Brain serotonin depletion and lesions of DRN increased the sodium appetite response, in basal conditions, after sodium depletion and hypovolemia or after beta-adrenergic stimulation as well. These observations raised the hypothesis that the suppression of ascending pathways from the DRN, possibly, 5-HTergic fibers, modifies the angiotensinergic or sodium sensing mechanisms of the subfornical organ involved in the control of the sodium appetite. 5-HTergic blockade in LPBN induced to similar results, particularly those regarded to the natriorexigenic response evoked by volume depletion or increase of the hypertonic saline ingestion induced by brain angiotensinergic stimulation. In conclusion, many evidences lead to acceptation of an integrated participation resulting of an interaction, between DRN and LPBN, for the sodium appetite control.

Este artigo revisa o papel do sistema serotoninérgico no controle do apetite ao sódio. Dados derivados da administração periférica e icv de agentes serotoninérgicos demonstraram a participação de receptores 5-HT2/3 na modulação do apetite ao sódio. Estas observações foram estendidas com os estudos realizados após a depleção cerebral de serotonina, lesões do NDR e durante o bloqueio 5-HT2A/2C no núcleo parabraquial lateral (NPBL). A depleção cerebral de serotonina e as lesões do NDR aumentaram o apetite ao sódio, em condições basais, após depleção de sódio, durante a hipovolemia ou após a estimulação beta-adrenérgica. Estas evidências suscitaram a hipótese de que a supressão de vias ascendentes do NDR, possivelmente 5-HT, alteram os mecanismos angiotensinérgicos e a atividade dos sensores de sódio do órgão subfornicial envolvidos no controle do apetite ao sódio. O bloqueio serotoninérgico no NPBL induziu a resultados similares, particularmente aqueles relacionados com a resposta natriorexigênica provocada pela depleção de volume ou o aumento da ingestão de salina hipertônica induzida pela estimulação angiotensinérgica cerebral. Em resumo, as evidências convergem para a admissão de uma participação integrada resultante da interação recíproca entre NDR e NPBL objetivando controlar o apetite ao sódio.

Behavioral and neuropharmacological evidence that serotonin crosses the blood-brain barrier in Coturnix japonica (Galliformes; Aves)

This study was carried out aiming to reach behavioral and neuropharmacological evidence of the permeability of the blood-brain barrier (BBB) to serotonin systemically administered in quails. Serotonin injected by a parenteral route (250-1000 æg.kg-1, sc) elicited a sequence of behavioral events concerned with a sleeping-like state. Sleeping-like behaviors began with feather bristling, rapid oral movements, blinking and finally crouching and closure of the eyes. Previous administration of 5-HT2C antagonist, LY53857 (3 mg.kg-1, sc) reduced the episodes of feather bristling and rapid oral movements significantly but without altering the frequency of blinking and closure of the eyes. Treatment with the 5-HT2A/2C antagonist, ketanserin (3 mg.kg-1, sc) did not affect any of the responses evoked by the serotonin. Quipazine (5 mg.kg-1, sc) a 5-HT2A/2C/3 agonist induced intense hypomotility, long periods of yawning-like and sleeping-like states. Previous ketanserin suppressed gaping responses and reduced hypomotility, rapid oral movements and bristling but was ineffective for remaining responses induced by quipazine. Results showed that unlike mammals, serotonin permeates the BBB and activates hypnogenic mechanisms in quails. Studies using serotoninergic agonist and antagonists have disclosed that among the actions of the serotonin, feather bristling, rapid oral movements and yawning-like state originated from activation of 5-HT2 receptors while blinking and closure of the eyes possibly require other subtypes of receptors.

Este estudo foi desenvolvido objetivando ampliar as evidências comportamentais e neurofarmacológicas da permeabilidade da barreira hematoencefálica (BHE) à serotonina administrada sistemicamente em codornas. A serotonina injetada por via parenteral (250-1000 æg.kg-1, sc) produziu uma seqüência de eventos relacionados com um estado semelhante ao sono. Comportamentos semelhantes ao sono começaram com o eriçamento das penas, movimentos orais rápidos, piscadelas e finalmente agachamento e fechamento dos olhos. A administração prévia do antagonista do receptor 5-HT2C, LY53857 (3 mg.kg-1, sc) reduziu significativamente os episódios de eriçamento das penas e movimentos orais rápidos, mas não alterou a freqüência de piscadelas e fechamento dos olhos. Tratamento com o antagonista do receptor 5-HT2A/2C, quetanserina (3 mg.kg-1, sc) não afetou nenhuma das respostas evocadas pela serotonina. A quipazina (5 mg.kg-1, sc), um agonista dos receptores 5-HT2A/2C/3, induziu intensa hipomotilidade e longos períodos de comportamentos semelhantes ao bocejo e ao sono. O tratamento prévio com quetanserina suprimiu as reações de bocejo e reduziu a hipomotilidade, os movimentos orais rápidos e as piscadelas, mas foi sem efeito para as demais respostas induzidas pela quipazina. Os resultados mostraram que, diferentemente dos mamíferos, a serotonina atravessa a BHE e ativa mecanismos hipnogênicos em codornas. Estudos com agonistas serotoninérgicos e antagonistas revelaram que, entre as ações da serotonina, o eriçamento das penas, os movimentos orais rápidos e o comportamento semelhante ao bocejo foram originados pela ativação de receptores 5-HT2, enquanto o piscar e o fechamento dos olhos possivelmente requereu outros subtipos de receptores.

An inhibitory compound against the interaction between Galpha(s) and the third intracellular loop region of serotonin receptor subtype 6 (5-HT(6)) disrupts the signaling pathway of 5-HT(6)

Serotonin receptor subtype 6 (5-HT(6)) is a neurotransmitter receptor, which is involved in various brain functions such as memory and mood. It mediates signaling via the interaction with a stimulatory G-protein. Especially, the third intracellular loop (iL3) of 5-HT(6) and the alpha subunit of stimulatory G protein (Galpha(s)) are responsible for the signaling process of 5-HT(6). Chemical compounds that could inhibit the interaction between the iL3 region of 5-HT(6) and Galpha(s) were screened from a chemical library consisted of 5,600 synthetic compounds. One of the identified compounds bound to Galpha(s) and effectively blocked the interaction between Galpha(s) and the iL3 region of 5-HT(6). The identified compound was further shown to reduce the serotonin-induced accumulation of cAMP in 293T cells transformed with 5-HT(6) cDNA. It also lowered the Ca2+ efflux induced by serotonin in cells expressing 5-HT(6) and chimeric Galpha(s5/q). These results indicate that the interaction between the iL3 of 5-HT(6) and Galpha(s) can be exploited for screening of regulatory compounds against the signaling pathway of 5-HT(6).

Haloperidol and clozapine differentially regulate signals pstream of glycogen synthase kinase 3 in the rat frontal cortex

Glycogen synthase kinase 3 (GSK3) was recently suggested to be a potential target of psychotropics used in psychiatric illnesses such as schizophrenia and bipolar disorder. Relevant studies have found that antipsychotic drugs regulate GSK3 activity via an increase in either inhibitory serine phosphorylation or amount of GSK3 after acute or subchronic treatment. Recent evidence shows that GSK3 is regulated by dopaminergic or serotonergic systems implicated in the pathophysiology and treatment mechanisms of schizophrenia and bipolar disorder. Therefore, antipsychotics may regulate GSK3 via antagonizing dopaminergic or serotonergic activity. However, the signaling pathway that is involved in GSK3 regulation by dopaminergic or serotonergic systems has not been well established. Haloperidol is a typical antipsychotic with potent dopamine D(2) receptor antagonism. Clozapine is an atypical antipsychotic with potent serotonin 5HT(2) receptor antagonism. We injected rats with haloperidol or clozapine and examined the phosphorylation and amount of GSK3alpha/beta and its well-known upstream regulators Akt and Dvl in the rat frontal cortex by Western blotting. Both haloperidol and clozapine induced Ser21/9 phosphorylation of GSK3GSK3alpha/beta. Haloperidol increased the Ser473 phosphorylation of Akt transiently, whereas clozapine maintained the increase for 1 h. Haloperidol did not affect the phosphorylation and amount of Dvl, whereas clozapine increased both phosphorylation and the amount of Dvl. Our results suggest that GSK3 activity may be regulated by both typical and atypical antipsychotics and that Akt or Dvl, depending on the D(2)- or 5HT(2)- receptor antagonism properties of typical and atypical antipsychotics, mediate the regulation differently.

Antiemetic effect of ondansetron and dexamethasone in gynecologic malignant patients receiving chemotherapy.

OBJECTIVES: To evaluate the antiemetic effect of a single dose of ondansetron and dexamethasone as a prophylaxis for chemotherapy induced acute nausea and emesis and factors associated with the control of acute nausea and emesis. MATERIAL AND METHOD: Patients who received single dose of 8 mg ondansetron and 20 mg dexamethasone as a prophylaxis for chemotherapy induced nausea and emesis at Department of Obstetrics and Gynecology, Bangkok Metropolitan Administration Medical College and Vajira Hospital, between October 2004 and April 2006 were identified. The assessment record of the drug efficacy had been evaluated in the first 24 hours after the start of chemotherapy in terms of control of vomiting, and nausea. Age of the patients, history of alcohol intake, type of cancer, regimen of chemotherapy and course of chemotherapy were analysed as possible factors associated with the control of nausea and emesis. RESULTS: Seventy-eight gynecologic-cancer patients receiving 353 cycles of chemotherapy were evaluated in this study. Completed control of acute vomiting and nausea were 68% and 57.2% respectively. Complete control of acute vomiting and nausea were 56.9% and 45.4% in patients of < or = 45 years compared to 78.8% and 68.7% in those with > 45 years. Complete control of acute vomiting and nausea were 59.2% and 48.7% in those receiving cisplatin-containing regimens compared to 86.7% and 75.2% in non-cisplatin containing regimens. Univariable and multivariable analysis showed that younger patients and those who received cisplatin-containing regimens had significant lower rates of complete control of both nausea and emesis. Patients receiving the first three courses of chemotherapy had significantly higher rate of complete control of nausea but not emesis as compared to those receiving chemotherapy after the third course. CONCLUSION: A single intravenous dose of 8 mg of ondansetron and 20 mg of dexamethasone had good control of acute nausea and vomiting only in those who received non-cisplatin containing regimens and those older than 45 years.

Evidence indicating participation of the serotonergic system in controlling feeding behavior in Coturnix japonica (Galliformes: Aves)

Investigamos a participação do sistema serotonérgico cerebral no controle da ingestão de alimento em codornas (Coturnix japonica) por meio da administração oral e sistêmica de precursores da serotonina. A suplementação dietética com triptofano (0,1-50,0 g/kg de ração) provocou inibição dose-dependente da ingestão de alimento em 5 h de avaliação, que se manteve ao final de 24 h com doses de 30,0 e 50,0 g/kg. Codornas tratadas com hidroxitriptofano (12,5-50,0 mg/kg, via intracoelomática) exibiram aguda inibição da ingestão alimentar, tanto as normoalimentadas quanto as submetidas ao jejum. Nas aves em jejum, a resposta hipofágica foi efetiva apenas quando a administração do precursor foi feita imediatamente antes da oferta de alimento. Resposta similar foi alcançada com a administração de serotonina (0,125-2,5 mg/kg, sc). Nos minutos iniciais após a administração desenvolveu-se resposta hipnogênica, implicando assunção de que essa amina atravessa a barreira hemato-encefálica em codornas, diferentemente do observado em mamíferos. A administração de hidroxitriptofano em todas as doses utilizadas induziu intensa resposta dipsogênica, não obstante o desenvolvimento concomitante de resposta hipnogênica. Os resultados sugerem o envolvimento de vias serotonérgicas no controle da ingestão de alimento em codornas e mostram pela primeira vez as ações hipnógena, induzida pela serotonina e hiperdipsética, pelo hidroxitriptofano.

Maternal aggression in Wistar rats: effect of 5-HT2A/2C receptor agonist and antagonist microinjected into the dorsal periaqueductal gray matter and medial septum

The objective of the present study was to assess the role of the 5-HT2A/2C receptor at two specific brain sites, i.e., the dorsal periaqueductal gray matter (DPAG) and the medial septal (MS) area, in maternal aggressive behavior after the microinjection of either a 5-HT2A/2C receptor agonist or antagonist. Female Wistar rats were microinjected on the 7th postpartum day with the selective agonist alpha-methyl-5-hydroxytryptamine maleate (5-HT2A/2C) or the antagonist 5-HT2A/2C, ketanserin. The agonist was injected into the DPAG at 0.2 (N = 9), 0.5 (N = 10), and 1.0 æg/0.2 æl (N = 9), and the antagonist was injected at 1.0 æg/0.2 æl (N = 9). The agonist was injected into the medial septal area (MS) at 0.2 (N = 9), 0.5 (N = 7), and 1.0 æg/0.2 æl (N = 6) and the antagonist was injected at 1.0 æg/0.2 æl (N = 5). For the control, saline was injected into the DPAG (N = 7) and the MS (N = 12). Both areas are related to aggressive behavior and contain a high density of 5-HT receptors. Non-aggressive behaviors such as horizontal locomotion (walking) and social investigation and aggressive behaviors such as lateral threat (aggressive posture), attacks (frontal and lateral), and biting the intruder were analyzed when a male intruder was placed into the female resident's cage. For each brain area studied, the frequency of the behaviors was compared among the various treatments by analysis of variance. The results showed a decrease in maternal aggressive behavior (number of bites directed at the intruder) after microinjection of the agonist at 0.2 and 1.0 æg/0.2 æl (1.6 ± 0.7 and 0.9 ± 0.3) into the DPAG compared to the saline group (5.5 ± 1.1). There was no dose-response relationship with the agonist. The present findings suggest that the 5-HT2A/2C receptor agonist has an inhibitory effect on maternal aggressive behavior when microinjected into the DPAG and no effect when microinjected into the MS. Ketanserin (1.0 æg/0.2 æl) decreased locomotion when microinjected into the DPAG and MS, but did not affect aggressive behavior. We interpret these findings as evidence for a specific role of 5-HT2A/2C receptors in the DPAG in the inhibition of female aggressive behavior, dissociated from those on motor activity.

Investigation of central mechanism of insulin induced hypoglycemic convulsions in mice.

Insulin produces seizures in healthy and diabetic animals. Amongst suggested mechanisms, the role of neuromodulators and neurotransmitters is not clear. The present study explores the mechanisms involved in insulin-induced convulsions. Convulsions were induced in Swiss male albino mice with graded doses of insulin. Blood sugar levels were measured prior to and after the first convulsion. Drugs like 5-HTP (5-HT precursor), pCPA (5-HT depletor), ondansetron (5-HT3 antagonist), ketanserin (5-HT, antagonist), ketamine (NMDA antagonist), 1-dopa (dopamine precursor) and reserpine (amine depletor) were studied for interaction with convulsive behaviour induced by insulin. Insulin in 2 IU/kg dose did not produce convulsions while 4 and 8 IU/kg doses produced convulsions in 50% and 100% of animals respectively. 5-HTP, ondansetron, ketanserin, ketamine and l-dopa significantly protected/inhibited animals from convulsions at all studied doses of insulin. On the contrary, pCPA and reserpine potentiated insulin induced convulsions. Insulin caused mortality in 40 and 100% animals with 4 and 8 IU/kg doses respectively. pCPA and reserpine treatments caused mortality at all doses of insulin, while other drugs did not influence insulin induced mortality. Blood sugar levels were reduced in all groups irrespective of the presence or absence of convulsions. A definitive link of serotonergic, dopaminergic and excitatory amino acid pathways in mediating insulin-induced hypoglycemic convulsions is suggested.

Involvement of 5-HT1A and 5-HT2 receptor in cisplatin induced emesis in dogs.

The effect of drug acting on 5-HT1A, 5-HT2 and 5-HT3 receptors were studied against cisplatin and apomorphine induced emesis in dogs. Buspirone, 5-HT1A receptor partial agonist significantly reduced the emetic episodes though it had no significant effect on emetic latency. Mianserin, 5-HT2 receptor antagonist exhibited significant reduction in emetic episodes and in latency. Buspirone prevented the apomorphine induced emesis while mianserin had no effect. The antiemetic activity of buspirone may be attributable to its agonistic activity at 5-HT1A receptor and antagonistic activity at dopamine receptors. These findings further confirm the involvement of 5-HT1A and 5-HT2 receptor in cytotoxic drug induced emesis, though the species difference in their antiemetic action can not be ruled out.

5-HT3 receptors in selective animal models of cognition.

Role of 5-HT3 receptors in cholinergic hypofunctional models of cognitive impairment in the elevated plus maze model and a passive avoidance model is studied. Cognitive impairment was caused by scopolamine (1 mg/kg, ip) in mice and 5-HT3 ligands mCPBG (1 and 5 mg/kg, ip) and ondansetron (0.5 and 5 mg/kg, ip) were administered before the pre-learning phase to study the effects on acquisition, while post-learning administration was used to determine the effects on consolidation. Ondansetron improved acquisition and retention in cholinergic hypofunctional models while mCPBG potentiated selected impaired cognitive indices. The results indicate the role of 5-HT3 receptors in cognition and that an ideal evaluation of 5-HT3 ligands in cognition should distinguish true cognitive effects from locomotor, motivational and emotional effects.

Effect of the intracerebroventricular administration of GR 113808, a selective 5-HT4 antagonist, on water intake during hyperosmolarity and hypovolemia

We demonstrate here that acute third ventricle injections of GR 113808, a highly selective 5-HT4 antagonist, decrease water intake induced by a previous salt load while potentiating drinking elicited by hypovolemia induced by previous subcutaneous administration of polyethylene glycol in male Wistar rats (200 + or - 20 g). At the dose of 160 nmol/rat, third ventricle injections of GR 113808 induced a significant reduction of water intake in salt-loaded animals after 120 min as compared to salt-loaded animals receiving third ventricle injections of saline (salt load + GR = 3.44 + or - 0.41 ml, N = 12; salt load + saline = 5.74 + or - 0.40 ml, N = 9). At the dose of 80 nmol/rat, GR 113808 significantly enhanced water intake in hypovolemic animals after 120 min as compared to hypovolemic animals receiving third ventricle injections of saline (hypovol + GR = 4.01 + or - 0.27 ml, N = 8; hypovol + saline = 2.41 + or - 0.23 ml, N = 12). We suggest that central 5-HT4 receptors may exert a positive drive on water intake due to hyperosmolarity and a negative input on drinking provoked by hypovolemia.

Strain-dependent effects of diazepam and the 5-HT2B/2C receptor antagonist SB 206553 in spontaneously hypertensive and Lewis rats tested in the elevated plus-maze

The 5-HT2B/2C receptor antagonist SB 206553 exerts anxiolytic effects in rat models of anxiety. However, these effects have been reported for standard rat strains, thus raising the issue of SB 206553 effects in rat strains displaying different levels of anxiety. Herein, the effects of SB 206553 in a 5-min elevated plus-maze test of anxiety were compared to those of the reference anxiolytic, diazepam, in two rat strains respectively displaying high (Lewis rats) and low (spontaneously hypertensive rats, SHR) anxiety. Diazepam (0.37, 0.75, or 1.5 mg/kg; 30 min before testing) increased in a dose-dependent manner the behavioral measures in SHR, but not in Lewis rats. On the other hand, SB 206553 (1.25, 2.5, or 5 mg/kg; 30 min before testing) failed to alter the anxiety parameters in both strains, whereas it increased closed arm entries in Lewis rats, suggesting that it elicited hyperactivity in the latter strain. Accordingly, the hypolocomotor effect of the nonselective 5-HT2B/2C receptor agonist m-chlorophenylpiperazine (1.5 mg/kg ip 20 min before a 15-min exposure to an activity cage) was prevented by the 1.25 and 2.5 mg/kg doses of SB 206553 in Lewis rats and SHR, respectively. Compared with SHR, Lewis rats may display a lower response to benzodiazepine-mediated effects and a more efficient control of locomotor activity by 5-HT2B/2C receptors

Serotonergic mechanism in imipramine induced antinociception in rat tail flick test.

Substantial evidence has accumulated that spinally projecting serotonergic neurons modulate nociception. However, the exact receptor subtypes that mediate the antinociceptive response of serotonin within the spinal cord continue to be a subject of debate. Therefore, we explored the effect of serotonergic system on imipramine induced antinociception by using 5-Hydroxytryptamine-3 (5HT3) receptor antagonist ondansetron and 5-Hydroxytryptamine-2 (5HT2) receptor antagonist mianserine, and depletion of brain 5-Hydroxytryptamine (5HT) with p-chlorophenyl alanine (PCPA). Male wistar strain rats were pretreated with either ondansetron (0.5 mg/kg, i.p.) or mianserine (1 mg/kg, i.p.). After 15 minutes, rats received injection of imipramine (10 mg/kg). Nociception was assessed by tail-flick method. Imipramine (2 mg, 5 mg, 10 mg, and 20 mg/kg) produce antinociceptive response in the dose dependent manner. Prior treatment with 5HT3 antagonist, Ondansetron and 5HT2 antagonist, mianserine reduce the antinociceptive response of imipramine. In PCPA treated rats imipramine (10 mg/kg) failed to produce antinociception. These results indicate that the 5HT plays an important role in imipramine induced antinociception.

Effect of the 5-HT3 receptor antagonist ondansetron on amphetamine-induced hyperactivity and stereotypy in rats.

The effects of different doses of ondansetron (0.1, 0.5, 1, 2 mg/kg) administered intra-peritoneally were studied on amphetamine-induced hyperactivity and stereotypy in wistar rats. Ondansetron was administered 30 minutes prior to d-amphetamine (3 mg/kg, i.p.). Ondansetron in doses of 0.5 and 1 mg/kg significantly decreased the mean number of head dippings and crossings in the hole board test and in doses of 0.1 and 0.5 mg/kg significantly decreased the average stereotypic score. Since the hyperactivity and stereotypy are dopamine mediated, the effect of ondansetron to reduce these states suggests a potential role for ondansetron in conditions with dopamine excess.

Sistema serotoninérgico: receptores e respostas funcionais / Brain serotonin system: receptors and functional response

A partir da síntese da serotonina, em 1951, iniciou-se a investigaçäo farmacológica dos receptores serotoninérgicos. A estimulaçäo dos mais variados tipos de receptores gera múltiplas respostas funcionais verificadas em nível de sistema nervoso central, terminaçöes nervosas serotoninérgicos em nível metabólico e fisiopatológico

Antinociception induced by stimulating amygdaloid nuclei in rats: changes produced by systemically administered antagonists

The antinociceptive effects of stimulating the medial (ME) and central (CE) nuclei of the amygdala in rats were evaluated by the changes in the latency for the tail withdrawal reflex to noxious heating of the skin. A 30-s period of sine-wave stimulation of the ME or CE produced a significant and short increase in the duration of tail flick latency. A 15-s period of stimulation was ineffective. Repeated stimulation of these nuclei at 48-h intervals produced progressively smaller effects. The antinociception evoked from the ME was significantly reduced by the previous systemic administration of naloxone, methysergide, atropine, phenoxybenzamine, and propranolol, but not by mecamylamine, all given at the dose of 1.0 mg/kg. Previous systemic administration of naloxone, atropine, and propranolol, but not methysergide, phenoxy-benzamine, or mecamylamine, was effective against the effects of stimulating the CE. We conclude that the antinociceptive effects of stimulating the ME involve at least opioid, serotonergic, adrenergic, and muscarinic cholinergic descending mechanisms. The effects of stimulating the CE involve at least opioid, beta-adrenergic, and muscarinic cholinergic descending mechanisms.

Central serotonergic and histaminergic modulation of peripheral inflammation and nociception in rats.

Possible central serotonergic and histaminergic modulation of acute peripheral inflammation was investigated in rats, adopting the formaldehyde-induced acute pedal inflammation as an experimental model. Intracerebroventricular (icv) administration of central inhibitory neurotransmitter, serotonin and its precursor, 5-hydroxytryptophan (5-HTP) attenuated the oedema volume and exudate protein content alongwith augmentation in pain threshold. On the contrary, cyproheptadine, a 5-HT-receptor antagonist and selective serotonin synthesis inhibitor, parachlorophenylalanine (PCPA) produced oedema augmenting and pro-nociceptive effects besides elevating the protein content of the exudate. Centrally administered histamine attenuated pedal oedema, nociception as well as protein concentration in oedema fluid. Cimetidine, an H2 histaminergic receptor blocker did not produce any significant effect on inflammation.

Effect of graded doses of methysergide on basal and pentagastrin stimulated gastric secretion in anaesthetised rats.

The effect of continuous infusion (iv) of graded doses of methysergide (0.1-50 microgram(s)/kg/hr) was studied on basal and pentagastrin (5 microgram(s)/kg/hr) stimulated gastric acid secretion in anaesthetised rats by the slow, continuous stomach perfusion method. Both basal and pentagastrin stimulated acid secretion indicated a biphasic response. Methysergide induced stimulation at a lower dose of 1 microgram(s)/kg/hr and inhibition at higher doses of 20-50 microgram(s)/kg/hr. The stimulatory effect may be due to postsynaptic receptor blockade while the inhibitory effect at higher dose may be due to blockade of presynaptic 5-HT autoreceptors, or due to a direct inhibitory effect of unknown basis.