Evaluation of the noradrenergic pathway and alpha-2 and beta-receptors in the modulation of the analgesia induced by transcutaneous electric nerve stimulation of high and low frequencies / Evaluación de la vía noradrenérgica y de los receptores alfa-2 y beta en la modulación de analgesia inducida por la estimulación eléctrica nerviosa transcutánea con alta y baja frecuencia / Avaliação da via noradrenérgica e dos receptores alfa-2 e beta na modulação da analgesia induzida pela estimulação elétrica nervosa transcutânea de alta e de baixa frequência

Transcutaneous electric nerve stimulation is a noninvasive method used in clinical Physiotherapy to control acute or chronic pain. Different theories have been proposed to explain the mechanism of the analgesic action of transcutaneous electric nerve stimulation, as the participation of central and peripheral neurotransmitters. The aim of this study was to evaluate the involvement of noradrenergic pathway and of the receptors alfa-2 and beta in the modulation of analgesia produced by transcutaneous electric nerve stimulation of high and low frequency in Wistar rats after chronic treatment with propranolol or yohimbine intraperitoneally. Animals weighing 200 to 300 g were divided into 9 groups (n=8), which were obtained nociceptive thresholds through the Tail Flick before and after application of TENS for comparing the change of pain. The administration of yohimbine or propranolol at a dose of 3 mg/kg was effective in antagonizing the analgesia induced by high (150 Hz) and low (10 Hz) frequency transcutaneous electric nerve stimulation according to ANOVA test followed by Duncan post hoc test (p<0.05). Thus, it is suggested the involvement of alpha-2 and beta noradrenergic receptors in the modulation of transcutaneous electric nerve stimulation-induced analgesia.

La estimulación eléctrica nerviosa transcutánea es un método no invasivo utilizado en la clínica de Fisioterapia para controlar el dolor agudo y crónico. Diversas teorías son propuestas para explanar el mecanismo de acción analgésico de la estimulación eléctrica nerviosa transcutánea, como la participación de neurotransmisores centrales y periféricos. El objetivo del presente estudio fue evaluar la participación de la vía noradrenérgica y de los receptores alfa-2 y beta en la modulación de analgesia inducida por la estimulación eléctrica nerviosa transcutánea con alta y baja frecuencia en ratos del tipo Wistar, después del tratamiento crónico con yohimbina o propranolol por la vía intraperitoneal. Animales que pesaban 200 y 300 g fueron divididos en nueve grupos (n=8), por los cuales fueron obtenidos los umbrales nociceptivos por medio del Tail Flick, antes y después de la aplicación de la estimulación eléctrica nerviosa transcutánea con el intuito de comparar la alteración del cuadro álgico. La administración de yohimbina o propranolol en el dosis de 3 mg/kg fue eficaz en resultar en una antagonización de analgesia inducida por la estimulación eléctrica nerviosa transcutánea con alta (150 Hz) y baja (10 Hz) frecuencia, de acuerdo al test de ANOVA seguido del test post-hoc de Duncan (p>0,05). Por lo tanto, se sugiere el envolvimiento de los receptores noradrenergicos alfa-2 y beta en la modulación de analgesia inducida por la estimulación eléctrica nerviosa transcutánea.

Estimulação elétrica nervosa transcutânea é um método não invasivo utilizado na clínica de Fisioterapia para controlar dores aguda ou crônica. Diferentes teorias são propostas para explicar o mecanismo de ação analgésica da estimulação elétrica nervosa transcutânea, como a participação de neurotransmissores centrais e periféricos. O objetivo do presente estudo foi avaliar a participação da via noradrenérgica e dos receptores alfa-2 e beta na modulação da analgesia induzida pela estimulação elétrica nervosa transcutânea de alta e baixa frequência em ratos Wistar, após tratamento crônico com ioimbina ou propranolol por via intraperitoneal. Animais pesando entre 200 e 300 g foram divididos em 9 grupos (n=8), dos quais se obteve os limiares nociceptivos por meio do Tail Flick antes e após a aplicação da estimulação elétrica nervosa transcutânea para comparação de mudança do quadro álgico. A administração de ioimbina ou de propranolol na dose de 3 mg/kg foi efetiva em causar uma antagonização da analgesia induzida pela estimulação elétrica nervosa transcutânea de alta (150 Hz) e baixa frequência (10 Hz) segundo teste ANOVA seguido do teste post hoc Duncan (p<0,05). Dessa forma, sugere-se o envolvimento de receptores noradrenérgicos alfa-2 e beta na modulação da analgesia induzida pela estimulação elétrica nervosa transcutânea. .

5-HT1A/1B, 5-HT6, and 5-HT7 serotonergic receptors recruitment in tonic-clonic seizure-induced antinociception: role of dorsal raphe nucleus.

Pharmacological studies have been focused on the involvement of different neural pathways in the organization of antinociception that follows tonic-clonic seizures, including 5-hydroxytryptamine (5-HT)-, norepinephrine-, acetylcholine- and endogenous opioid peptide-mediated mechanisms, giving rise to more in-depth comprehension of this interesting post-ictal antinociceptive phenomenon. The present work investigated the involvement of 5-HT(1A/1B), 5-HT(6), and 5-HT(7) serotonergic receptors through peripheral pretreatment with methiothepin at doses of 0.5, 1.0, 2.0 and 3.0 mg/kg in the organization of the post-ictal antinociception elicited by pharmacologically (with pentylenetetrazole at 64 mg/kg)-induced tonic-clonic seizures. Methiothepin at 1.0 mg/kg blocked the post-ictal antinociception recorded after the end of seizures, whereas doses of 2.0 and 3.0 mg/kg potentiated the post-ictal antinociception. The nociceptive thresholds were kept higher than those of the control group. However, when the same 5-hydroxytryptamine receptors antagonist was microinjected (at 1.0, 3.0 and 5.0 microg/0.2 microL) in the dorsal raphe nucleus, a mesencephalic structure rich in serotonergic neurons and 5-HT receptors, the post-ictal hypo-analgesia was consistently antagonized. The present findings suggest a dual effect of methiothepin, characterized by a disinhibitory effect on the post-ictal antinociception when peripherally administered (possibly due to an antagonism of pre-synaptic 5-HT(1A) serotonergic autoreceptors in the pain endogenous inhibitory system) and an inhibitory effect (possibly due to a DRN post-synaptic 5-HT(1B), 5-HT(6), and 5-HT(7) serotonergic receptors blockade) when centrally administered. The present data also suggest that serotonin-mediated mechanisms of the dorsal raphe nucleus exert a key-role in the modulation of the post-ictal antinociception.

Involvement of 5-HT(2) serotonergic receptors of the nucleus raphe magnus and nucleus reticularis gigantocellularis/paragigantocellularis complex neural networks in the antinociceptive phenomenon that follows the post-ictal immobility syndrome.

The post-ictal immobility syndrome is followed by a significant increase in the nociceptive thresholds in animals and men. In this interesting post-ictal behavioral response, endogenous opioid peptides-mediated mechanisms, as well as cholinergic-mediated antinociceptive processes, have been suggested. However, considering that many serotonergic descending pathways have been implicated in antinociceptive reactions, the aim of the present work is to investigate the involvement of 5-HT(2)-serotonergic receptor subfamily in the post-ictal antinociception. The analgesia was measured by the tail-flick test in seven or eight Wistar rats per group. Convulsions were followed by statistically significant increase in the tail-flick latencies (TFL), at least for 120 min of the post-ictal period. Male Wistar rats were submitted to stereotaxic surgery for introduction of a guide-cannula in the rhombencephalon, aiming either the nucleus raphe magnus (NRM) or the gigantocellularis complex. In independent groups of animals, these nuclei were neurochemically lesioned with a unilateral microinjection of ibotenic acid (1.0 microg/0.2 microL). The neuronal damage of either the NRM or nucleus reticularis gigantocellularis/paragigantocellularis complex decreased the post-ictal analgesia. Also, in other independent groups, central administration of ritanserin (5.0 microg/0.2 microL) or physiological saline into each of the reticular formation nuclei studied caused a statistically significant decrease in the TFL of seizing animals, as compared to controls, in all post-ictal periods studied. These results indicate that serotonin input-connected neurons of the pontine and medullarly reticular nuclei may be involved in the post-ictal analgesia.

Dorsal raphe nucleus and locus coeruleus neural networks and the elaboration of the sweet-substance-induced antinociception.

In order to investigate the effects of monoaminergic neurons of the dorsal raphe nucleus (DRN) and locus coeruleus (LC) on the elaboration and control of sweet-substance-induced antinociception, male albino Wistar rats weighing 180-200 g received sucrose solution (250 g/L) for 7-14 days as their only source of liquid. After the chronic consumption of sucrose solution, each animal was pretreated with unilateral microinjection of ibotenic acid (1.0 microg/0.2 microL) in the DRN or in the LC. The tail withdrawal latencies of the rats in the tail-flick test were measured immediately before and 7 days after this treatment. The neurochemical lesion of locus coeruleus, but not of DRN neural networks with ibotenic acid, after the chronic intake of sweetened solution, decreased the sweet-substance-induced antinociception. These results indicate the involvement of noradrenaline-containing neurons of the LC in the sucrose-induced antinociception. We also consider the possibility of DRN serotonergic neurons exerting some inhibitory effect on the LC neural networks involved with the elaboration of the sweet-substance-induced antinociception.

Estudo do envolvimento de vias oradrenérgicas, e de receptores alfa beta das redes neurais do locus coeruleus na analgesia pós-ictal

Tem sido proposto que o estado pós-ictal geralmente é seguido de antinocicepção. Alguns trabalhos descrevem que este comportamento é eliciado pela estimulação de estruturas localizadas no tronco encefálico, como o núcleo dorsal da rafe, magno da rafe, gigantocelular e substância cinzenta periaquedutal, profundamente interconectados, através de uma via endógena inibitória da dor, que integra várias redes neurais em seu percurso descendente. Com efeito, demonstrou-se que há conexões entre o núcleo magno da rafe e a substância cinzenta periaquedutal com o locus coeruleus e, considerando ser este núcleo majoritariamente noradrenérgico, se aceita amplamente que tais neurônios monoaminérgicos participam na modulação da dor, exercendo um importante controle descendente da via nociceptiva ascendente. Nesse trabalho, objetivou-se estudar aspectos da neuroquímica da analgesia induzida por convulsões produzidas por drogas, utilizando-se lesão neurotóxica (ácido ibotênico) do locus coeruleus (LC). Também foi investigado o papel do mecanismo noradrenérgico neste processo antinociceptivo, com a administração de antagonistas noradrenérgicos -ioimbina (alfa IND.2) e propranolol (beta) -por via intraperitonial e central tendo esta, por alvo, as redes neurais do locus coeruleus. O pentilenotetrazol (PTZ), um antagonista não-competitivo, que impede o influxo de Cl POT. - mediado pelo GABA, foi usado em um modelo experimental de crises convulsivas para avaliar as características neuroquímicas da analgesia pós ictal. As lesões no locus coeruleus, com ácido ibotênico causaram uma diminuição estatisticamente significante da analgesia pós-ictal em todos os animais estudados, quando comparado ao grupo controle. A administração dos antagonistas noradrenérgicos ioimbina (alfa IND.2) e propanolol (beta), tanto por via intraperitonial, quanto central, produziu uma redução estatisticamente significante na analgesia...(AU)