The neurotoxic mechanism of Jack Bean Urease in insects involves the interplay between octopaminergic and dopaminergic pathways.

In the last decades, the entomotoxicity of JBU and its derived peptides became an object of study, due mainly to the ubiquitous interaction of these compounds with different species of insects and their potential as natural insecticides. In this work, we investigated the neurotoxic effects of JBU in Nauphoeta cinerea cockroaches by dissecting pharmacologically the monoaminergic pathways involved. Selective pharmacological modulators for monoaminergic pathways in in vivo and ex vivo experimental models were employed. Thus, the analysis of N. cinerea neurolocomotory behavior demonstrated that JBU (1.5 and 3 µg/g) induces a significant decrease in the exploratory activity. In these assays, pretreatment of animals with phentolamine, SCH23390 or reserpine, interfered significantly with the response of JBU. Using in vivo abductor metathoracic preparations JBU (1.5 µg/g) induced progressive neuromuscular blockade, in 120 min recordings. In this set of experiments, the previous treatment of the animals with phentolamine, SCH23390 or reserpine, completely inhibited JBU-induced neuromuscular blockade. The recordings of spontaneous compound neural action potentials in N. cinerea legs showed that JBU, only in the smallest dose, significantly decreased the number of potentials in 60 min recordings. When the animals were pretreated with phentolamine, SCH23390, or reserpine, but not with mianserin, there was a significant prevention of the JBU-inhibitory responses on the action potentials firing. Meanwhile, the treatment of the animals with mianserin did not affect JBU's inhibitory activity. The data presented in this work strongly suggest that the neurotoxic response of JBU in N. cinerea involves a cross talking between OCTOPAMIN-ergic and DOPAMIN-ergic nerve systems, but not the SEROTONIN-ergic neurotransmission. Further molecular biology studies with expression of insect receptors associated with voltage clamp techniques will help to discriminate the selectivity of JBU over the monoaminergic transmission.

The Octopamine Receptor Is a Possible Target for Eugenol-Induced Hyperactivity in the Blood-Sucking Bug Triatoma infestans (Hemiptera: Reduviidae).

Eugenol is a major component of the essential oils in cloves and other aromatic plants. In insects, it produces toxic effects and repellency, and there is evidence that its site of action is the octopamine receptor. The objective of the present study was to explore whether the octopamine receptor is involved in the hyperactivity produced by eugenol in the blood-sucking bug Triatoma infestans (Klug). This insect is the main vector of Chagas disease in Latin America. Four treatments were topically applied on third instar nymphs: 1) octopamine, 2) eugenol, 3) phentolamine hydrochloride (an antagonist of the octopamine receptor) followed by octopamine, and 4) phentolamine hydrochloride followed by eugenol. Both octopamine and eugenol hyperactivated the nymphs. However, pretreatment with phentolamine hydrochloride inhibited the hyperactivating effect of both compounds. These results are in agreement with previous works on Drosophila melanogaster (Meigen) (Diptera: Drosophilidae) and the American cockroach. They suggest that the octopamine receptor is a possible site of action for eugenol.

Avaliação do potencial antirreabsortivo de géis de fentolamina e propranolol em reimplantes dentários / Evaluation of the anti-resorptive potential of phentolamine and propranolol gels on tooth replantation

Este trabalho teve como objetivo avaliar os efeitos da aplicação tópica de fármacos bloqueadores adrenérgicos (AR) sobre o processo de reparo periodontal de dentes reimplantados em ratos. Inicialmente, cultura de fibroblastos do ligamento periodontal humano foi utilizada para avaliar qualitativamente a citotoxicidade de soluções etanólicas de fentolamina (bloqueador α-AR) e propranolol (bloqueador ßAR) em diferentes doses (0,75 µg/mL, 2,5 µg/mL, 10 µg/mL e 100 µg/mL), após 24 horas de exposição. Posteriormente, modelo animal de avulsão e reimplante dentário foi utilizado para avaliar o potencial antirreabsortivo do bloqueio adrenérgico local com géis de fentolamina (F) ou propranolol (P), em excipiente de carboximetilcelulose (CMC). Incisivos superiores direitos foram extraídos de 48 ratos Wistar machos, armazenados em guardanapo de papel por 30 minutos, e distribuídos aleatoriamente em oito grupos (n=6) de acordo com a medicação intracanal: F0.75, F10 e F100 receberam gel de fentolamina nas concentrações 0,75 µg/mL, 10 µg/mL e 100 µg/mL, respectivamente; P2.5, P10 e P100 receberam gel de propranolol nas concentrações 2,5 µg/mL, 10 µg/mL e 100 µg/mL, respectivamente; HC e CMC receberam pasta de hidróxido de cálcio e gel de carboximetilcelulose, respectivamente. Os animais foram eutanasiados 30 dias após o reimplante e as seguintes análises foram realizadas: microtomografia (volume, superfície, proporção e densidade de tecido mineralizado), histomorfometria (áreas de reabsorção radicular inflamatória, reabsorção por substituição, anquilose e reparo periodontal) e histoquímica (atividade osteoclástica). Os dados foram analisados estatisticamente por meio de ANOVA e teste de Tukey ou Kruskal Wallis e teste de Dunn, de acordo com sua normalidade (α=5%). A análise qualitativa da viabilidade celular demonstrou que a dose de 100 µg/mL dos fármacos apresentou alta citotoxicidade, com 100% das células inviáveis, e as demais doses propiciaram viabilidade celular semelhante. As análises microtomográfica e histomorfométrica das amostras in vivo não revelaram qualquer diferença estatística significante entre os fármacos testados e suas diferentes doses (p>0,05). No entanto, P10 e F10 apresentaram qualitativamente um melhor resultado, pois foram os únicos grupos classificados com áreas de intenso reparo periodontal (P10) e de discreta reabsorção radicular inflamatória (F10 e P10). O tratamento com F10 e P10 diminuiu significativamente o número de osteoclastos em comparação com as outras medicações tópicas (p<0,05). Concluiu-se que a aplicação tópica de géis de fentolamina e propranolol na dose de 10 µg/mL diminuiu significativamente a atividade osteoclástica sem causar efeitos citotóxicos.(AU)

This study aimed to evaluate the effects of topical application of adrenergic (AR) blocking drugs on the periodontal repair process of replanted teeth in rats. First, culture of human periodontal ligament fibroblasts was used to qualitatively assess the cytotoxicity of ethanolic solutions of phentolamine (α-AR blocker) and propranolol (ßAR blocker) at different doses (0.75 µg/mL, 2.5 µg/mL, 10 µg/mL and 100 µg/mL) after 24 hours of exposure. Then, animal model of tooth avulsion and replantation was used to evaluate the anti-resorptive potential of local adrenergic blockade with phentolamine (Ph) or propranolol (Pr) gels, in carboxymethylcellulose excipient (CMC). Maxillary right incisors were extracted from 48 male Wistar rats, stored in paper napkins for 30 minutes, and randomly distributed into eight groups (n = 6) according to intracanal medication: Ph0.75, Ph10 and Ph100 received phentolamine gel at concentrations of 0.75 µg/mL, 10 µg/mL and 100 µg/mL, respectively; Pr2.5, Pr10 and Pr100 received propranolol gel at concentrations of 2.5 µg/mL, 10 µg/mL and 100 µg/mL, respectively; CH and CMC received calcium hydroxide paste and carboxymethylcellulose gel, respectively. The animals were euthanized 30 days after replantation and the following analyzes were performed: microtomography (volume, surface, proportion and density of mineralized tissue), histomorphometry (areas of inflammatory root resorption, replacement root resorption, ankylosis and periodontal repair) and histochemistry (osteoclastic activity). Data were analyzed statistically by means of ANOVA and Tukey's test or Kruskal Wallis and Dunn's test, according to their normality (α = 5%). The qualitative analysis of cell viability demonstrated that the dose of 100 µg/mL of the drugs presented high cytotoxicity, with 100% of the cells non-viable, and the other doses provided similar cell viability. Microtomographic and histomorphometric analyzes of in vivo samples did not reveal any significant statistical difference between the tested drugs and their different doses (p>0.05). However, Pr10 and Ph10 presented qualitatively a better result, as they were the only groups classified with areas of intense periodontal repair (Pr10) and discrete inflammatory root resorption (Ph10 and Pr10). Treatment with Ph10 and Pr10 significantly decreased the number of osteoclasts compared to the other topical medications (p<0.05). It was concluded that topical application of phentolamine and propranolol gels at a dose of 10 µg/mL significantly decreased osteoclastic activity without causing cytotoxic effects(AU)

Electrical field-induced contractions on Crotalus durissus terrificus and Bothrops jararaca aortae are caused by endothelium-derived catecholamine.

Endothelium is the main source of catecholamine release in the electrical-field stimulation (EFS)-induced aortic contractions of the non- venomous snake Panterophis guttatus. However, adrenergic vasomotor control in venomous snakes such as Crotalus durissus terrificus and Bothrops jararaca has not yet been investigated. Crotalus and Bothrops aortic rings were mounted in an organ bath system. EFS-induced aortae contractions were performed in the presence and absence of guanethidine (30 µM), phentolamine (10 µM) or tetrodotoxin (1 µM). Frequency-induced contractions were also performed in aortae with endothelium removed. Immunohistochemical localization of both tyrosine hydroxylase (TH) and S-100 protein in snake aortic rings and brains, as well as in human tissue (paraganglioma tumour) were carried out. EFS (4 to 16 Hz) induced frequency-dependent aortic contractions in both Crotalus and Bothrops. The EFS-induced contractions were significantly reduced in the presence of either guanethidine or phentolamine in both snakes (p<0.05), whereas tetrodotoxin had no effect in either. Removal of the endothelium abolished the EFS-induced contractions in both snakes aortae (p<0.05). Immunohistochemistry revealed TH localization in endothelium of both snake aortae and human vessels. Nerve fibers were not observed in either snake aortae. In contrast, both TH and S100 protein were observed in snake brains and human tissue. Vascular endothelium is the main source of catecholamine release in EFS-induced contractions in Crotalus and Bothrops aortae. Human endothelial cells also expressed TH, indicating that endothelium- derived catecholamines possibly occur in mammalian vessels.

Entomotoxic activity of Rhinella icterica (Spix, 1824) toad skin secretion in Nauphoeta cinerea cockroaches: An octopamine-like modulation.

Rhinella icterica is a poisonous toad whose toxic secretion has never been studied against entomotoxic potential. Sublethal doses of Rhinella icterica toxic secretion (RITS) were assayed in Nauphoeta cinerea cockroaches, in order to understand the physiological and behavioral parameters, over the insect central and peripheral nervous system. RITS (10 µg/g) injections, induced behavioral impairment as evidenced by a significant decrease (38 ±â€¯14%) in the distance traveled (p < .05), followed by an increase (90 ±â€¯6%) of immobile episodes (p < .001, n = 28, respectively). In cockroaches semi-isolated heart preparations, RITS (16 µg/200 µl) induced a significant irreversible dose-dependent negative chronotropism, reaching ~40% decrease in heart rate in 20 min incubation. In in vivo cockroach neuromuscular preparations, RITS (20, 50 and 100 µg/g of animal weight) induced a time-dependent inhibition of twitch tension that was complete for 20 µg/g, in 120 min recordings. RITS (10 µg/g) also induced a significant increase in the insect leg grooming activity (128 ±â€¯10%, n = 29, p < .01), but not in the antennae counterparts. The RITS increase in leg grooming activity was prevented in 90% by the pretreatment of cockroaches with phentolamine (0.1 µg/g). The electrophysiological recordings of spontaneous neural compound action potentials showed that RITS (20 µg/g) induced a significant increase in the number of events, as well as in the rise time and duration of the potentials. In conclusion, RITS showed to be entomotoxic, being the neuromuscular failure and cardiotoxic activity considered the main deleterious effects. The disturbance of the cockroaches' behavior together with the electrophysiological alterations, may unveil the presence of some toxic components present in the poison with inherent biotechnological potentials.

Electrical field stimulation-induced contractions on Pantherophis guttatus corpora cavernosa and aortae.

A tetrodotoxin (TTX)-resistant mechanism is responsible for the electrical field stimulation (EFS)-induced contractions and relaxations of Crotalus durissus terrificus corpora cavernosa. Here it was investigated whether this mechanism also occurs in corpora cavernosa and aortae of the non-venomous snake Pantherophis guttatus corpora cavernosa and aortae. Corpora cavernosa and aortic rings isolated from Pantherophis guttatus snake were mounted in organ bath system for isometric tension recording. EFS-induced contractions in both tissues were performed in the presence and absence of guanethidine (30 µM), phentolamine (10 µM) and tetrodotoxin (1 µM). In another set of experiments, the endothelium was removed from aortic rings and EFS-induced contractions were performed in the denuded rings. Electrical field stimulation-induced contractions were frequency-dependent in Pantherophis guttatus corpora cavernosa and aortic rings. The contractions were significantly reduced in the presence of guanethidine (30 µM) or phentolamine (10 µM). Pre-treatment with tetrodotoxin had no effect on the EFS-induced contractions of either corpora cavernosa or aortic rings. Surprisingly, the EFS-induced contractions of aortic rings denuded of endothelium were almost abolished. These results indicate that the TTX-resistant mechanism is present in EFS-induced contractions of Pantherophis guttatus corpora cavernosa and aortae. The experiments performed in the aorta indicate that the endothelium is the main source for the release of catecholamines induced by EFS.

Anti-inflammatory effects of propranolol in the temporomandibular joint of female rats and its contribution to antinociceptive action.

BACKGROUND: ß-Blockers reduce temporomandibular joint (TMJ) pain. We asked whether they also reduce TMJ inflammation and, if so, whether this anti-inflammatory effect contributes to its analgesic action. METHODS: We measured many parameters of the inflammatory response after co-administration of the ß-blocker propranolol with the inflammatory agent carrageenan in the TMJ of female rats. We also hypothesized that the activation of ß-adrenoceptors in the TMJ induces nociception mediated, at least in part, by the inflammatory response. To test this hypothesis, we examined the nociceptive response induced by the activation of the ß-adrenoceptors in the TMJ in female rats pretreated with thalidomide and fucoidan. RESULTS: We found that the co-administration of propranolol with carrageenan in the TMJ of female rats significantly reduced several parameters of the inflammatory response induced by carrageenan such as plasma extravasation, neutrophil migration and the release of the pro-inflammatory cytokines TNF-α, IL-1ß and CINC-1. Furthermore, the injection of the ß-adrenergic receptor agonist isoproterenol in the TMJ induced nociception that was significantly reduced by thalidomide, fucoidan and by the co-administration of propranolol but not of the α-adrenergic receptor antagonist phentolamine. CONCLUSIONS: Propranolol has anti-inflammatory effects that contribute to its antinociceptive action in the TMJ of females. SIGNIFICANCE: ß-Blockers have an anti-inflammatory effect on temporomandibular joint (TMJ) that contributes to its analgesic effect. The results of this work suggest that ß-blockers can be used to treat the painful conditions of TMJ, especially when they are associated with an inflammatory process.

O estresse crônico e a via de sinalização adrenérgica no desenvolvimento da lesão periapical / Chronic stress and the adrenergic signaling pathway on the development of periapical lesion

Os objetivos deste estudo são: 1) Esclarecer a possível associação entre o estresse crônico e a estimulação do Sistema Nervoso Simpático (SNS) e investigar sua interferência no desenvolvimento e progressão da lesão periapical; 2) Avaliar a quantidade de receptores para os neurotransmissores na região periapical; 3) Elucidar uma via farmacológica de modulação inflamatória através do uso de bloqueadores adrenérgicos. Trinta e dois ratos Wistar foram submetidos à modelo animal de lesão periapical através da exposição da cavidade pulpar e em seguida foram aleatoriamente divididos em 4 grupos: sem estresse (NS); estresse + solução salina (SS); estresse + ß-bloqueador (Sß); estresse + α-bloqueador (Sα). Os grupos SS, Sß e Sα foram submetidos à modelo animal de estresse crônico durante 28 dias e receberam injeções diárias de solução salina, propranolol (ß bloqueador adrenérgico) e fentolamina (α bloqueador adrenérgico), respectivamente. Após 28 dias os animais foram eutanasiados e procedeu-se as seguintes análises: a) dos níveis séricos de corticosterona através de Radioimunoensaio; b) histomorfométrica por coloração com hematoxilina e eosina; c) da estrutura óssea periapical através de microtomografia computadorizada (micro-CT); d) expressão de receptores ß e α adrenérgicos; e) da atividade osteoclástica através de histoquímica para fosfatase ácida resistente ao tartarato (TRAP). Os resultados obtidos mostram um aumento do nível sérico de corticosterona dos animais do grupo SS sendo estatisticamente significante comparados aos animais do grupo NS (sem estresse) (p<.05). Nenhuma diferença estatística foi observada a nível histológico uma vez que todos os animais apresentaram infiltrado inflamatório moderado e área de lesão periapical similares. A análise por micro-CT também mostrou similaridade da área e volume da lesão periapical em todos grupos. Através da histoquímica para TRAP verificou-se uma quantidade significativamente menor de osteoclastos nos grupos que receberam bloqueadores adrenérgicos (Sß e Sα) (p<.05). Conclui-se que não houve influência significativa do estresse crônico no desenvolvimento e progressão da lesão periapical e a administração de bloqueadores adrenérgicos apesar de não ter sido capaz de modular a resposta inflamatória, diminuiu significativamente o número de osteoclastos na região periapical(AU)

The objectives of this study are: 1) To clarify the possible association between chronic stress (CS) and stimulation of the Sympathetic Nervous System (SNS) and to investigate its interference in the development and progression of periapical lesion; 2) To evaluate the amount of receptors for neurotransmitters in the periapical region; 3) To elucidate a pharmacological pathway of inflammatory modulation through the use of adrenergic blockers. Thirty- two Wistar rats were submitted to animal model of periapical lesion through exposure of the pulp cavity and were then randomly divided into 4 groups: no stress (NS); stress + saline solution (SS); stress + ß-blocker (Sß); stress + α-blocker (Sα). The SS, Sß and Sα groups were submitted to animal model of CS for 28 days and received daily injections of saline solution, propranolol (ß blocker adrenergic) and phentolamine (α adrenergic blocker), respectively. After 28 days the animals were euthanized and the following analysis were carried out: a) serum corticosterone levels through Radioimmunoassay; b) histomorphometric by staining with hematoxylin and eosin; c) periapical bone structure through micro computed tomography; d) expression of ß and α adrenergic receptors; e) osteoclast activity by histochemistry for tartrate resistant acid phosphatase (TRAP). The results obtained show an increase in the seric corticosterone level of the animals of the SS group being statistically significant compared to the NS group animals (without stress). No statistical difference was observed histologically since all animals had moderate inflammatory infiltrate and similar periapical lesion area. Micro-CT analysis also showed similarity of the area and volume of the periapical lesion in all groups. Through histochemistry for TRAP, a significantly lower amount of osteoclasts was observed in the groups receiving adrenergic blockers (Sß and Sα). It was concluded that there was no significant influence of chronic stress on the development and progression of the periapical lesion and the administration of adrenergic blockers despite not being able to modulate the inflammatory response, significantly decreased the number of osteoclasts in the periapical region(AU)

Hyperalgesic effect of subarachnoid administration of phentolamine in mice / Hyperalgesic effect of subarachnoid administration of phentolamine in mice / Efecto hiperalgésico de la fentolamina por vía subaracnoidea en ratones

BACKGROUND AND OBJECTIVES: Painful phenomenon is one of the most important and complex experiences. Phentolamine is a non-selective alpha-adrenergic antagonist. The objective of this study was to compare the effect of increasing doses of phentolamine into subarachnoid space in rats in the modulation of painful phenomenon. METHODS: 84 male Wistar rats were divided into formalin and plantar incision groups, subdivided into six subgroups (n = 7). Control group received only saline (10 µL); active subgroups received phentolamine 10 µmg (GF10), 20 mg (GF20), 30 mg (GF30), 40 mg (GF40), and 50 g (GF50). In formalin group, pain was induced by injection of 50 µL of 2% formalin in dorsal region of right posterior paw. In plantar incision group, pain was induced by plantar incision and evaluated using von Frey filaments. Induction and maintenance of anesthesia were performed with 3% halothane for catheter placement into subarachnoid space and plantar incision. Statistical analysis was performed using the JMP program from SAS with 5% significance level. RESULTS: Phentolamine at doses of 20 and 30 g increased the algesic response in the intermediate phase of the formalin test. In plantar incision test, it had hyperalgic effect on first, third, fifth, and seventh days at a dose of 10 g and on first, third, and fifth days at a dose of 20 g and on fifth day at a dose of 30 g. CONCLUSION: Subarachnoid administration of phentolamine showed hyperalgesic effect, possibly due to the involvement of different subclasses of alpha-adrenergic receptors in modulating pain pathways. .

JUSTIFICATIVA E OBJETIVOS: O fenômeno doloroso é uma das mais importantes e complexas experiências. A fentolamina é antagonista alfa-adrenérgico não seletivo. O objetivo foi comparar os efeitos de doses crescentes da fentolamina, por via subaracnóidea, em ratos na modulação do fenômeno doloroso. MÉTODO: Foram usados 84 ratos Wistar machos, divididos nos grupos formalina e incisão plantar, subdivididos em seis subgrupos (n = 7). No subgrupo controle (GC) apenas salina (10 µL), nos subgrupos ativos, 10 µg de fentolamina (GF10), 20 µg (GF20), 30 µg (GF30), 40 µg (GF40) e 50 µg (GF50). No grupo formalina, a dor foi induzida com injeção de 50 µL de formalina a 2%, na região dorsal da pata posterior direita. No grupo incisão plantar, a dor foi induzida por incisão plantar e avaliação pelos filamentos de Von Frey. Indução e manutenção anestésica com halotano a 3% para introdução de cateter no espaço subaracnóideo e feitura da incisão plantar. Análise estatística dos resultados pelo programa JMP do SAS com nível de significância 5%. RESULTADOS: A fentolamina nas doses de 20 e 30 µg produziu aumento da resposta álgica na fase intermediária do teste da formalina. No teste da incisão plantar, promoveu efeito hiperálgico no primeiro, terceiro, quinto e sétimo dias na dose de 10 µg, no primeiro, terceiro e quinto dias na dose de 20 µg e no quinto dia na dose de 30 µg. CONCLUSÃO: A fentolamina por via subaracnóidea promoveu efeito hiperálgico, possivelmente pela participação de diferentes subclasses de receptores alfa-adrenérgicos nas vias modulatórias da dor. .

JUSTIFICACIÓN Y OBJETIVOS: El fenómeno doloroso es una de las más importantes y complejas experiencias. La fentolamina es un antagonista alfaadrenérgico no selectivo. El objetivo fue comparar los efectos de dosis crecientes de fentolamina por vía subaracnoidea en la modulación del fenómeno doloroso en ratones. MÉTODO: Fueron usados 84 ratones Wistar machos, divididos en los grupos formalina e incisión plantar, subdivididos en 6 subgrupos (n = 7). En el subgrupo control (GC) solamente se administró solución salina (10 µL); en los subgrupos activos, 10 µg de fentolamina (GF10), 20 µg (GF20), 30 µg (GF30), 40 µg (GF40) y 50 µg (GF50). En el grupo formalina, el dolor fue inducido con una inyección de 50 µL de formalina al 2% en la región dorsal de la pata posterior derecha. En el grupo incisión plantar, el dolor se indujo por incisión plantar y evaluación por los filamentos de Von Frey. La inducción y el mantenimiento anestésico se llevó a cabo con halotano al 3% para la introducción de catéter en el espacio subaracnoideo y la realización de la incisión plantar. El análisis estadístico de los resultados se hizo mediante el programa JMP(r) del SAS con un nivel de significación del 5%. RESULTADOS: La fentolamina en las dosis de 20 y 30 µg produjo un aumento de la respuesta de dolor en la fase intermedia del test de la formalina. En el test de la incisión plantar, generó un efecto hiperalgésico en el primero, tercero, quinto y séptimo días con dosis de 10 µg; en el primero, tercero y quinto días con dosis de 20 µg; y en el quinto día con dosis de 30 µg. CONCLUSIÓN: La fentolamina por vía subaracnoidea generó un efecto hiperalgésico posiblemente por la participación de diferentes subclases de receptores alfaadrenérgicos en las vías moduladoras del dolor. .

Modulatory effects of taurine on jejunal contractility

Taurine (2-aminoethanesulfonic acid) is widely distributed in animal tissues and has diverse pharmacological effects. However, the role of taurine in modulating smooth muscle contractility is still controversial. We propose that taurine (5-80 mM) can exert bidirectional modulation on the contractility of isolated rat jejunal segments. Different low and high contractile states were induced in isolated jejunal segments of rats to observe the effects of taurine and the associated mechanisms. Taurine induced stimulatory effects on the contractility of isolated rat jejunal segments at 3 different low contractile states, and inhibitory effects at 3 different high contractile states. Bidirectional modulation was not observed in the presence of verapamil or tetrodotoxin, suggesting that taurine-induced bidirectional modulation is Ca2+ dependent and requires the presence of the enteric nervous system. The stimulatory effects of taurine on the contractility of isolated jejunal segments was blocked by atropine but not by diphenhydramine or by cimetidine, suggesting that muscarinic-linked activation was involved in the stimulatory effects when isolated jejunal segments were in a low contractile state. The inhibitory effects of taurine on the contractility of isolated jejunal segments were blocked by propranolol and L-NG-nitroarginine but not by phentolamine, suggesting that adrenergic β receptors and a nitric oxide relaxing mechanism were involved when isolated jejunal segments were in high contractile states. No bidirectional effects of taurine on myosin phosphorylation were observed. The contractile states of jejunal segments determine taurine-induced stimulatory or inhibitory effects, which are associated with muscarinic receptors and adrenergic β receptors, and a nitric oxide associated relaxing mechanism.

Modulatory effects of taurine on jejunal contractility.

Taurine (2-aminoethanesulfonic acid) is widely distributed in animal tissues and has diverse pharmacological effects. However, the role of taurine in modulating smooth muscle contractility is still controversial. We propose that taurine (5-80 mM) can exert bidirectional modulation on the contractility of isolated rat jejunal segments. Different low and high contractile states were induced in isolated jejunal segments of rats to observe the effects of taurine and the associated mechanisms. Taurine induced stimulatory effects on the contractility of isolated rat jejunal segments at 3 different low contractile states, and inhibitory effects at 3 different high contractile states. Bidirectional modulation was not observed in the presence of verapamil or tetrodotoxin, suggesting that taurine-induced bidirectional modulation is Ca(2+) dependent and requires the presence of the enteric nervous system. The stimulatory effects of taurine on the contractility of isolated jejunal segments was blocked by atropine but not by diphenhydramine or by cimetidine, suggesting that muscarinic-linked activation was involved in the stimulatory effects when isolated jejunal segments were in a low contractile state. The inhibitory effects of taurine on the contractility of isolated jejunal segments were blocked by propranolol and L-NG-nitroarginine but not by phentolamine, suggesting that adrenergic ß receptors and a nitric oxide relaxing mechanism were involved when isolated jejunal segments were in high contractile states. No bidirectional effects of taurine on myosin phosphorylation were observed. The contractile states of jejunal segments determine taurine-induced stimulatory or inhibitory effects, which are associated with muscarinic receptors and adrenergic ß receptors, and a nitric oxide associated relaxing mechanism.

Norepinephrine depresses the nitric oxide production in the ascidian hemocytes.

Norepinephrine (NE) is a neuro-hormone released by vertebrates and invertebrates during acute stress, and can influence their immune function. We found that NE depressed the production of nitric oxide (NO) by the hemocytes of ascidians. Our results with a fluorescent indicator for NO in assays using both NE and either α or ß-antagonist revealed that NE down-regulated NO production by the ascidian hemocytes. Our data suggest that NE may be acting via specific hemocyte receptors to induce a decrease in immune function.

Mechanisms of blunted muscle vasodilation during peripheral chemoreceptor stimulation in heart failure patients.

We described recently that systemic hypoxia provokes vasoconstriction in heart failure (HF) patients. We hypothesized that either the exaggerated muscle sympathetic nerve activity and/or endothelial dysfunction mediate the blunted vasodilatation during hypoxia in HF patients. Twenty-seven HF patients and 23 age-matched controls were studied. Muscle sympathetic nerve activity was assessed by microneurography and forearm blood flow (FBF) by venous occlusion plethysmography. Peripheral chemoreflex control was evaluated through the inhaling of a hypoxic gas mixture (10% O(2) and 90% N(2)). Basal muscle sympathetic nerve activity was greater and basal FBF was lower in HF patients versus controls. During hypoxia, muscle sympathetic nerve activity responses were greater in HF patients, and forearm vasodilatation in HF was blunted versus controls. Phentolamine increased FBF responses in both groups, but the increase was lower in HF patients. Phentolamine and N(G)-monomethyl-l-arginine infusion did not change FBF responses in HF but markedly blunted the vasodilatation in controls. FBF responses to hypoxia in the presence of vitamin C were unchanged and remained lower in HF patients versus controls. In conclusion, muscle vasoconstriction in response to hypoxia in HF patients is attributed to exaggerated reflex sympathetic nerve activation and blunted endothelial function (NO activity). We were unable to identify a role for oxidative stress in these studies.

Autonomic regulation of mechanical properties in porcine mitral valve cusps.

BACKGROUND: The presence of nerves in heart valves was first depicted decades ago and identified into subpopulations: sympathetic, parasympathetic. So valves are expected to be greatly affected by the autonomic nerves. However, few studies have focused on the regulation of heart valves by the autonomic nervous system. OBJECTIVE: We sought to identify the role of the autonomic nervous system in the regulation of the mechanical properties of porcine mitral valve tissues. METHODS: Mechanical properties of porcine mitral valve leaflets were evaluated in response to norepinephrine (NE) and acetylcholine (ACH), the main neurotransmitters. At the same time, phentolamine (Phent), metoprolol (Metop), atropine (Atrop) and endothelial denudation were added to the reactive system. RESULTS: Under physiological conditions, the stiffness was not affected by endothelial denudation (p > 0.05). NE elevated the valve stiffness significantly per 10-fold increase in concentration (10(-6) vs 10(-7), p < 0.05; 10(-5) vs 10(-6), p < 0.05). This response was mitigated by Phent, Metop or endothelial denudation (p < 0.05), however, it was still increased significantly when compared to Controls (p < 0.05). ACH caused a decrease in stiffness accompanied by an increase in its concentration (significant change in stiffness per 10-fold increase in ACH concentration, 10(-6) vs Control, p < 0.05; 10(-5) vs 10(-6), p < 0.05), which were reversed by endothelial denudation and Atrop (p > 0.05 vs Control). CONCLUSION: These findings highlight the role of the autonomic nervous system in the regulation of the mechanical properties of porcine mitral valve cusps, which underline the importance of autonomic nervous status for optimal valve function.

Both α1- and ß1-adrenoceptors in the bed nucleus of the stria terminalis are involved in the expression of conditioned contextual fear.

BACKGROUND AND PURPOSE: The bed nucleus of the stria terminalis (BNST) is a limbic structure that is involved in the expression of conditioned contextual fear. Among the numerous neural inputs to the BNST, noradrenergic synaptic terminals are prominent and some evidence suggests an activation of this noradrenergic neurotransmission in the BNST during aversive situations. Here, we have investigated the involvement of the BNST noradrenergic system in the modulation of behavioural and autonomic responses induced by conditioned contextual fear in rats. EXPERIMENTAL APPROACH: Male Wistar rats with cannulae bilaterally implanted into the BNST were submitted to a 10 min conditioning session (6 footshocks, 1.5 ma/ 3 s). Twenty-four hours later freezing and autonomic responses (mean arterial pressure, heart rate and cutaneous temperature) to the conditioning box were measured for 10 min. The adrenoceptor antagonists were administered 10 min before the re-exposure to the aversive context. KEY RESULTS: L-propranolol, a non-selective ß-adrenoceptor antagonist, and phentolamine, a non-selective α-adrenoceptor antagonist, reduced both freezing and autonomic responses induced by aversive context. Similar results were observed with CGP20712, a selective ß(1) -adrenoceptor antagonist, and WB4101, a selective α(1) -antagonist, but not with ICI118,551, a selective ß(2) -adrenoceptor antagonist or RX821002, a selective α(2) -antagonist. CONCLUSIONS AND IMPLICATIONS: These findings support the idea that noradrenergic neurotransmission in the BNST via α(1) - and ß(1) -adrenoceptors is involved in the expression of conditioned contextual fear.

Regulação autonômica das propriedades mecânicas em bioprótese valvar porcina / Autonomic regulation of mechanical properties in porcine mitral valve cusps / Regulación autonómica de las propiedades mecánicas en bioprótesis valvular porcina

FUNDAMENTO: A presença de nervos nas válvulas cardíacas foi demonstrada pela primeira vez há décadas e identificadas em subpopulações: simpáticas e parassimpáticas, e, portanto, é esperado que as válvulas sejam grandemente afetadas pelos nervos autônomos. Entretanto, poucos estudos têm se concentrado na regulação de válvulas cardíacas pelo sistema nervoso autônomo. OBJETIVO: Buscamos identificar o papel do sistema nervoso autônomo na regulação das propriedades mecânicas dos tecidos de válvulas mitrais porcinas. MÉTODOS: As propriedades mecânicas dos folhetos de válvulas mitrais porcinas foram avaliados em resposta à norepinefrina (NE) e acetilcolina (ACH), os principais neurotransmissores. Ao mesmo tempo, fentolamina (FENT), metoprolol (Metop), atropina (Atrop) e desnudamento endotelial foram adicionados ao sistema reativo. RESULTADOS: Sob condições fisiológicas, a rigidez não foi afetada pelo desnudamento endotelial (p > 0,05). A NE significantemente aumentou a rigidez valvar por aumento de 10 vezes na concentração (10-6 vs 10-7, p < 0,05; 10-5 vs 10-6, p < 0,05). Essa resposta foi amenizada por FENT, Metop ou desnudamento endotelial (p < 0,05); entretanto, manteve-se aumentada de maneira significante quando comparada aos Controles (p < 0,05). A ACH causou uma diminuição na rigidez acompanhada por um aumento em sua concentração (alteração significante na rigidez por aumento de 10 vezes na concentração de ACH, 10-6 vs Controle, p < 0,05; 10-5 vs 10-6, p < 0,05), que foi revertida pelo desnudamento endotelial e Atrop (p > 0,05 vs Controle). CONCLUSÃO: Esses achados ressaltam o papel do sistema nervoso autônomo na regulação das propriedades mecânicas das cúspides de válvula mitral porcina, o que reforça a importância do estado nervoso autônomo no funcionamento ideal da válvula.

BACKGROUND: The presence of nerves in heart valves was first depicted decades ago and identified into subpopulations: sympathetic, parasympathetic. So valves are expected to be greatly affected by the autonomic nerves. However, few studies have focused on the regulation of heart valves by the autonomic nervous system. OBJECTIVE: We sought to identify the role of the autonomic nervous system in the regulation of the mechanical properties of porcine mitral valve tissues. METHODS: Mechanical properties of porcine mitral valve leaflets were evaluated in response to norepinephrine (NE) and acetylcholine (ACH), the main neurotransmitters. At the same time, phentolamine (Phent), metoprolol (Metop), atropine (Atrop) and endothelial denudation were added to the reactive system. RESULTS: Under physiological conditions, the stiffness was not affected by endothelial denudation (p > 0.05). NE elevated the valve stiffness significantly per 10-fold increase in concentration (10-6 vs 10-7, p < 0.05; 10-5 vs 10-6, p < 0.05). This response was mitigated by Phent, Metop or endothelial denudation (p < 0.05), however, it was still increased significantly when compared to Controls (p < 0.05). ACH caused a decrease in stiffness accompanied by an increase in its concentration (significant change in stiffness per 10-fold increase in ACH concentration, 10-6 vs Control, p < 0.05; 10-5 vs 10-6, p < 0.05), which were reversed by endothelial denudation and Atrop (p > 0.05 vs Control). CONCLUSION: These findings highlight the role of the autonomic nervous system in the regulation of the mechanical properties of porcine mitral valve cusps, which underline the importance of autonomic nervous status for optimal valve function.

FUNDAMENTO: La presencia de nervios en las válvulas cardíacas quedó demostrada por primera vez hace algunas décadas e identificadas en sub-poblaciones: simpáticas y parasimpáticas y por lo tanto, lo que se espera es que las válvulas reciban una gran afectación de los nervios autónomos. Sin embargo, pocos estudios se han concentrado en la regulación de válvulas cardíacas a través del sistema nervioso autónomo. OBJETIVO: Buscamos identificar el papel del sistema nervioso autónomo en la regulación de las propiedades mecánicas de los tejidos de las válvulas mitrales porcinas. MÉTODOS: Las propiedades mecánicas de las capas de válvulas mitrales porcinas fueron evaluadas en respuesta a la norepinefrina (NE) y a la acetilcolina (ACH), los principales neurotransmisores. Igualmente, la fentolamina (FENT), el metoprolol (Metop), la atropina (Atrop) y la denudación endotelial también se añadieron al sistema reactivo. RESULTADOS: Bajo condiciones fisiológicas, la rigidez no se afectó por el denudación endotelial (p > 0,05). La NE aumentó significativamente la rigidez valvular con un aumento de 10 veces en la concentración (10-6 vs 10-7, p < 0,05; 10-5 vs 10-6, p < 0,05). Esa respuesta fue amenizada por FENT, Metop o denudación endotelial (p < 0,05); pero se mantuvo aumentada de manera significativa cuando se le comparó con los Controles (p < 0,05). La ACH causó una disminución en la rigidez acompañada por un aumento en su concentración (alteración significativa en la rigidez por el aumento en 10 veces de la concentración de ACH, 10-6 vs Control, p < 0,05; 10-5 vs 10-6, p < 0,05), que fue revertida por la denudación endotelial y Atrop (p > 0,05 vs Control). CONCLUSIÓN: Esos hallazgos destacan el rol del sistema nervioso autónomo en la regulación de las propiedades mecánicas de las cúspides de la válvula mitral porcina, lo que refuerza la importancia del estado nervioso autónomo en el funcionamiento ideal de la válvula.

Effect of dehydroleucodine on intestinal transit: structural basis of the interaction with the α(2)-adrenergic receptor.

The activity of dehydroleucodine, a sesquiterpene lactone obtained from Artemisia douglasiana, was studied in mice small intestinal transit. Its mechanism was evaluated in the presence of several adrenergic and cholinergic antagonist drugs and one opioid antagonist. Docking of dehydroleucodine into the homology model of the α2-adrenergic receptor allowed us to analyze the structural basis of their interactions. The experiments showed that dehydroleucodine delayed intestinal transit. The docking of dehydroleucodine showed a unique binding site, equivalent to the binding site of carozolol in the ß-adrenergic receptor. The results suggested that dehydroleucodine produced an inhibitory effect on intestinal transit. Its action could be mediated, at least in part, through the α2-adrenergic receptor.

Subarachnoid serotonergic and noradrenergic antagonists increase the pain response in rats.

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 formalin 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 formalin 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%. 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.

Efeito vasomotor após intoxicação aguda com bupivacaína e levobupivacaína via intraperitoneal em ratos, analisado por imagem infravermelha digital / Vasomotor effect after acute intoxication with bupivacaine and levobupivacaine in rats via intraperitoneal route analyzed via digital infrared imaging

JUSTIFICATIVA E OBJETIVOS: O estudo do efeito vasomotor dos anestésicos locais (AL) é de suma importância para a análise da ocorrência de efeitos cardiotóxicos, neurotóxicos e interações medicamentosas. Com a finalidade de encontrar um fármaco mais seguro do que a bupivacaína racêmica, o presente estudo teve por objetivo a análise por imagem infravermelha digital do efeito vasomotor da intoxicação aguda da bupivacaína e da levobupivacaína via intraperitoneal em ratos. MÉTODO: Utilizaram-se 30 ratos machos da linhagem Wistar, alocados em três grupos (n = 10) e submetidos a uma injeção intraperitoneal de AL. No Grupo C (Controle), foi realizada injeção intraperitoneal de soro fisiológico 0,9 por cento 1 mL. No Grupo B (bupivacaína), injeção intraperitoneal de bupivacaína racêmica a 0,5 por cento (R50-S50), dose de 20 mg.kg-1 de peso. No Grupo L (levobupivacaína), injeção intraperitoneal de levobupivacaína a 0,5 por cento, excesso enantiomérico (S75-R25) em dose de 20 mg.kg-1 de peso. Procedeu-se à filmagem termográfica contínua desde o momento da pré-injeção até 30 minutos após a injeção. Os resultados das filmagens foram analisados em forma gráfica, verificando-se a temperatura máxima de cada rato e a temperatura média do sistema que abrigava o animal. RESULTADOS: Os resultados da análise gráfica revelaram que não houve diferença entre o Grupo L e o Grupo C, e a temperatura média permaneceu estável durante todo o experimento em ambos os grupos. No Grupo B, houve um fenômeno de aumento de temperatura após a injeção intraperitoneal de bupivacaína. CONCLUSÕES: Os resultados demonstraram que o efeito vasomotor da toxicidade aguda da levobupivacaína foi semelhante ao Grupo C com soro fisiológico, por meio de estudos macroscópicos por filmagem digital infravermelha, e que houve alterações vasomotoras (vasoconstrição) com a intoxicação por bupivacaína em relação ao Grupo C e em relação ao Grupo L.

BACKGROUND AND OBJECTIVES: The study of the vasomotor effect of local anesthetics (LA) is of paramount importance for the analysis of the occurrence of cardiotoxic and neurotoxic effects, and drug interactions. In order to find a safer drug than racemic bupivacaine, this study aimed to analyze digital infrared imaging of acute vasomotor effect of bupivacaine and levobupivacaine in rats intraperitoneally. METHOD: We used 30 male Wistar rats distributed into three groups (n = 10) and subjected to an intraperitoneal injection of LA. In Group C (control) 1 mL 0.9 percent saline was injected intraperitoneally. In Group B (bupivacaine), intraperitoneal injection of 0.5 percent of racemic bupivacaine (S50-R50), dose of 20 mg.kg-1 of body weight. In Group L (levobupivacaine), intraperitoneal injection of levobupivacaine 0.5 percent enantiomeric excess (S75-R25) in dose of 20 mg.kg-1 of body weight. The procedure was thermographicly continuously filmed from the time of pre-injection until 30 minutes after injection. The results of the recordings were analyzed in graphical form, verifying the maximum temperature of each rat and the average temperature of the system that housed the animal. RESULTS: The results of graphic analysis showed no difference between Group L and Group C, and the average temperature remained stable through-out the experiment in both groups. In Group B, there was a phenomenon of temperature increase after intraperitoneal injection of bupivacaine. CONCLUSIONS: The results demonstrated that the vasomotor effect of the acute toxicity of levobupivacaine was similar to Group C with saline, through macroscopic studies by infrared digital filmmaking, and that there were vasomotor changes (vasoconstriction), with bupivacaine intoxication in relation to both Group C and Group L.

JUSTIFICATIVA Y OBJETIVOS: El estudio del efecto vasomotor de los anestésicos locales (AL), es de suma importancia para el análisis del aparecimiento de efectos cardiotóxicos, neurotóxicos e interacciones medicamentosas. Con el fin de encontrar un fármaco más seguro que la bupivacaína racémica, el presente estudio se propuso analizar por imagen infrarroja digital, el efecto vasomotor de la intoxicación aguda de la bupivacaína y de la levobupivacaína vía intraperitoneal en ratones. MÉTODO: Fueron usados 30 ratones machos de la raza Wistar, divididos en tres grupos (n = 10) y sometidos a una inyección intraperitoneal de AL. En el Grupo C (Control), fue realizada una inyección intraperitoneal de suero fisiológico al 0,9 por ciento 1 mL. En el Grupo B (bupivacaína), una inyección intraperitoneal de bupivacaína racémica al 0,5 por ciento (R50-S50), dosis de 20 mg.kg-1 de peso. En el Grupo L (levobupivacaína), una inyección intraperitoneal de levobupivacaína al 0,5 por ciento, con exceso enantiomérico (S75-R25) en dosis de 20 mg.kg-1 de peso. Después de procedió a la filmación termográfica continua desde el momento anterior a la inyección hasta 30 minutos después de ella. Los resultados de las filmaciones se analizaron de forma gráfica, verificando la temperatura máxima de cada ratón y la temperatura promedio del sistema que abrigaba al animal. RESULTADOS: Los resultados del análisis gráfico revelaron que no hubo diferencia entre el Grupo L y el Grupo C, y que la temperatu-ra promedio se mantuvo estable durante todo el experimento en los dos grupos. En el Grupo B, se produjo un fenómeno de aumento de temperatura después de la inyección intraperitoneal de bupivacaína. CONCLUSIONES: Los resultados demostraron que el efecto vasomotor de la toxicidad aguda de la levobupivacaína fue similar al Grupo C con suero fisiológico, por medio de estudios macroscópicos por filmación digital infrarroja, y que se produjeron alteraciones vasomotoras (vasoconstricción)...

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.