RESUMO
BACKGROUND: Calcitonin gene-related peptide (CGRP) plays a major role in the pathogenesis of migraine and other primary headaches. Spinal trigeminal neurons integrate nociceptive afferent input from trigeminal tissues including intracranial afferents, and their activity is thought to reflect facial pain and headache in man. CGRP receptor inhibitors and anti-CGRP antibodies have been demonstrated to be therapeutically effective in migraine. In parallel, CGRP receptor inhibition has been shown to lower spinal trigeminal neuron activity in animal models of meningeal nociception. METHODS: In a rat model of meningeal nociception, single cell activity of neurons in the spinal trigeminal nucleus with meningeal afferent input was recorded to test a further pharmacological approach, scavenging CGRP with a CGRP-binding L-RNA oligonucleotide, the L-aptamer NOX-C89. Cumulative ascending doses of NOX-C89 were intravenously infused. RESULTS: Spontaneous activity of spinal trigeminal neurons did not change after 0.05 mg/kg NOX-C89, however, after additional infusion of 0.5 mg/kg and 5 mg/kg NOX-C89, spontaneous activity was dose-dependently reduced. Identical doses of a control L-aptamer had no effect. This pharmacological effect of NOX-C89 was observed 10-25 min after infusion, but no difference was detected in the period 0-5 min. For comparison, the previously investigated CGRP receptor antagonist olcegepant had reduced activity within 5 min after infusion. Alongside the reduced spontaneous activity, after infusion of NOX-C89 the heat-induced neuronal activity was abolished. CONCLUSIONS: Scavenging CGRP by mirror-image RNA aptamers provides further evidence that this approach can be used to control spinal trigeminal activity.
Assuntos
Aptâmeros de Nucleotídeos/farmacologia , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Meninges , Transtornos de Enxaqueca/tratamento farmacológico , Neurônios/efeitos dos fármacos , Nociceptividade/efeitos dos fármacos , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismo , Núcleo Espinal do Trigêmeo/efeitos dos fármacos , Animais , Aptâmeros de Nucleotídeos/administração & dosagem , Modelos Animais de Doenças , Masculino , RNA , Ratos , Ratos WistarRESUMO
Psychoactive substances affecting the dopaminergic system induce locomotor activation and, in high doses, stereotypies. Network mechanisms underlying the shift from an active goal-directed behavior to a "seemingly purposeless" stereotypic locomotion remain unclear. In the present study we sought to determine the relationships between the behavioral effects of dopaminergic drugs and their effects on local field potentials (LFPs), which were telemetrically recorded within the ventral tegmental area (VTA) of freely moving rats. We used the D2/D3 agonist quinpirole in a low, autoreceptor-selective (0.1 mg/kg, i.p.) and in a high (0.5 mg/kg, i.p.) dose, and a moderate dose of cocaine (10 mg/kg, i.p.). In the control group, power spectrum analysis revealed a prominent peak of LFP power in the theta frequency range during active exploration. Cocaine alone stimulated locomotion, but had no significant effect on the peak of the LFP power. In contrast, co-administration of low dose quinpirole with cocaine markedly altered the pattern of locomotion, from goal-directed exploratory behavior to recurrent motion resembling locomotor stereotypy. This behavioral effect was accompanied by a shift of the dominant theta power toward a significantly lower (by â¼15%) frequency. High dose quinpirole also provoked an increased locomotor activity with signs of behavioral stereotypies, and also induced a shift of the dominant oscillation frequency toward the lower range. These results demonstrate a correlation between the LFP oscillation frequency within the VTA and a qualitative aspect of locomotor behavior, perhaps due to a variable level of coherence of this region with its input or output areas.
Assuntos
Autorreceptores/metabolismo , Ondas Encefálicas/fisiologia , Cocaína/farmacologia , Locomoção/fisiologia , Receptores de Dopamina D2/metabolismo , Área Tegmentar Ventral/metabolismo , Animais , Autorreceptores/agonistas , Ondas Encefálicas/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Masculino , Microeletrodos , Ratos , Ratos Wistar , Receptores de Dopamina D2/agonistas , Área Tegmentar Ventral/efeitos dos fármacosRESUMO
Anxiety disorders are known to be comorbid with migraine, and cortical spreading depression (CSD) is the most likely cause of the migraine aura. To search for possible correlations between susceptibility to CSD and anxiety we used the open field test in male Sprague-Dawley rats chronically treated with the preventive anti-migraine drugs valproate or riboflavin. Animals avoiding the central area of the open field chamber and those with less exploratory activity (i.e. rearing) were considered more anxious. After 4 weeks of treatment CSDs were elicited by application of 1M KCl over the occipital cortex and the number of CSDs occurring over a 2h period was compared to the previously assessed open field behavior. Higher anxiety-like behavior was significantly correlated with a higher frequency of KCl-induced CSDs. In saline-treated animals, fewer rearings were found in animals with more frequent CSDs (R=-1.00). The duration of ambulatory episodes in the open field center correlated negatively with number of CSDs in the valproate group (R=-0.83; p<0.005) and in riboflavin treated group (R=-0.69; p<0.05) as well as total time spent in the open field center in both groups (R=-0.75; p<0.05 and R=-0.58; p<0.1 respectively). These results suggest that anxiety symptoms are associated with susceptibility to CSD and might explain why it can be an aggravating factor in migraine with aura.
Assuntos
Comportamento Animal/fisiologia , Depressão Alastrante da Atividade Elétrica Cortical/efeitos dos fármacos , Cloreto de Potássio/farmacologia , Animais , Antimaníacos/farmacologia , Ansiedade/psicologia , Eletrodos Implantados , Eletrofisiologia/métodos , Masculino , Transtornos de Enxaqueca/prevenção & controle , Atividade Motora/efeitos dos fármacos , Lobo Occipital/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Riboflavina/farmacologia , Ácido Valproico/farmacologia , Vitaminas/farmacologiaRESUMO
Cocaine (benzoylmethylecgonine), a natural alkaloid, is a powerful psychostimulant and a highly addictive drug. Unfortunately, the relationships between its behavioral and electrophysiological effects are not clear. We investigated the effects of cocaine on the firing of midbrain dopaminergic (DA) neurons, both in anesthetized and awake rats, using pre-implanted multielectrode arrays and a recently developed telemetric recording system. In anesthetized animals, cocaine (10 mg/kg, intraperitoneally) produced a general decrease of the firing rate and bursting of DA neurons, sometimes preceded by a transient increase in both parameters, as previously reported by others. In awake rats, however, injection of cocaine led to a very different pattern of changes in firing. A decrease in firing rate and bursting was observed in only 14% of DA neurons. Most of the other DA neurons underwent increases in firing rate and bursting: these changes were correlated with locomotor activity in 52% of the neurons, but were uncorrelated in 29% of them. Drug concentration measurements indicated that the observed differences between the two conditions did not have a pharmacokinetic origin. Taken together, our results demonstrate that cocaine injection differentially affects the electrical activity of DA neurons in awake and anesthetized states. The observed increases in neuronal activity may in part reflect the cocaine-induced synaptic potentiation found ex vivo in these neurons. Our observations also show that electrophysiological recordings in awake animals can uncover drug effects, which are masked by general anesthesia.
Assuntos
Potenciais de Ação/efeitos dos fármacos , Cocaína/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Mesencéfalo/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Neurônios Dopaminérgicos/fisiologia , Masculino , Mesencéfalo/fisiologia , Ratos , Ratos Wistar , Vigília/efeitos dos fármacosRESUMO
OBJECTIVE: Afferent information from the heart and the lung is conveyed to the brainstem by primary afferent fibers originating from vagal sensory neurons (jugular-nodose ganglion complex, JNC). The present study was made to evaluate if release of the sensory neuropeptide calcitonin gene-related peptide (CGRP) from the JNC can be used as a model for future studies on changes in neuropeptide release under pathological conditions of the heart. METHODS: Freshly isolated rat JNC's were passed through a series of solutions based on oxygenated synthetic interstitial fluid (SIF). Substances such as the TRPV1 receptor agonist capsaicin and the nitric oxide (NO) donor sodium nitroprusside (SNP) were added as excitatory test stimuli. The eluates were processed using an enzyme immuno-assay (EIA) for measurement of CGRP concentrations. Immunohistochemistry was used to visualize CGRP containing and NO producing neurons in the JNC. RESULTS: Both SNP and capsaicin caused significant increases in CGRP release. CGRP-immunoreactive neurons (somata) were preferentially found in the jugular ganglion, whereas neurons immunoreactive for neuronal NO synthase were mostly localized in the nodose ganglion. CONCLUSION: The present study demonstrates an easily reproducible model for measuring stimulated CGRP release from vagal afferents arising from the JNC. Nitric oxide produced by vagal afferents may stimulate CGRP release upon afferent activation.
Assuntos
Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Coração/inervação , Neurônios Aferentes/fisiologia , Gânglio Nodoso/metabolismo , Nervo Vago/citologia , Animais , Capsaicina/metabolismo , Masculino , Neurônios Aferentes/citologia , Doadores de Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo I/metabolismo , Nitroprussiato/metabolismo , Gânglio Nodoso/citologia , Ratos , Ratos Wistar , Fármacos do Sistema Sensorial/metabolismo , Nervo Vago/metabolismoRESUMO
Calcitonin gene-related peptide (CGRP) has been suggested to play a major role in the pathogenesis of migraines and other primary headaches. CGRP may be involved in the control of neuronal activity in the spinal trigeminal nucleus (STN), which integrates nociceptive afferent inputs from trigeminal tissues, including intracranial afferents. The activity of STN neurons is thought to reflect the activity of central trigeminal nociceptive pathways causing facial pain and headaches in humans. In a rat model of meningeal nociception, single neuronal activity in the STN was recorded. All units had receptive fields located in the exposed parietal dura mater. Heat and cold stimuli were repetitively applied to the dura in a fixed pattern of ramps and steps. The nonpeptide CGRP receptor antagonist BIBN4096BS was topically applied onto the exposed dura or infused intravenously. BIBN4096BS (300 microg/kg, i.v.) reduced spontaneous activity by approximately 30%, the additional dose of 900 microg/kg intravenously by approximately 50% of the initial activity, whereas saline had no effect. The activity evoked by heat ramps was also reduced after BIBN4096BS (900 microg/kg, i.v.) by approximately 50%. Topical administration of BIBN4096BS (1 mm) did not significantly change the spontaneous neuronal activity within 15 min. We conclude that the endogenous release of CGRP significantly contributes to the maintenance of spontaneous activity in STN neurons. Blockade of CGRP receptors, possibly at central and peripheral sites, may therefore be an effective way to decrease nociceptive transmission. This may offer a new therapeutic strategy for the treatment of facial pain and primary headaches.
Assuntos
Meninges/fisiologia , Neurônios/fisiologia , Piperazinas/farmacologia , Quinazolinas/farmacologia , Núcleo Espinal do Trigêmeo/fisiologia , Vias Aferentes/efeitos dos fármacos , Vias Aferentes/fisiologia , Animais , Peptídeo Relacionado com Gene de Calcitonina/análogos & derivados , Dura-Máter/fisiologia , Estimulação Elétrica , Eletrofisiologia , Masculino , Neurônios/efeitos dos fármacos , Ratos , Ratos Wistar , Técnicas Estereotáxicas , Núcleo Espinal do Trigêmeo/efeitos dos fármacosRESUMO
Nitric oxide is thought to control transmitter release and neuronal activity in the spinal dorsal horn and the spinal trigeminal nucleus, where nociceptive information from extra- and intracranial tissues is processed. Extracellular impulse activity was recorded from neurons in the rat spinal trigeminal nucleus with afferent input from the cranial dura mater. In contrast to the inactive isomer D-NAME, infusion of the nitric oxide synthase inhibitor L-NAME (20 mg/kg) significantly reduced neuronal activity and increased systemic blood pressure. It is concluded that nitric oxide production contributes to the ongoing activity of sensitized neurons in the spinal trigeminal nucleus. The results suggest that nitric oxide may be involved in the generation and maintenance of primary headaches such as migraine.
Assuntos
Potenciais de Ação/fisiologia , Meninges/enzimologia , Neurônios/enzimologia , Óxido Nítrico Sintase/antagonistas & inibidores , Núcleo Espinal do Trigêmeo/enzimologia , Potenciais de Ação/efeitos dos fármacos , Animais , Inibidores Enzimáticos/farmacologia , Masculino , Meninges/efeitos dos fármacos , NG-Nitroarginina Metil Éster/farmacologia , Neurônios/efeitos dos fármacos , Óxido Nítrico Sintase/metabolismo , Ratos , Ratos Wistar , Núcleo Espinal do Trigêmeo/efeitos dos fármacosRESUMO
In acute experiments on nembutal-urethan-anaesthetized rats, a slow infusion of subseptic dose of lipopolysaccharide (LPS) Escherichia coli (1 mg/ml) via the right jugular vein immediately led to bradycardia and extrasystoles. Preliminary administration of 20 mg/kg N(G)-nitro-L-arginine methyl ester (L-NAME) or 30 mg/kg aminoguanidine hydrochloride prevented the LPS-induced extrasystoles but did not affect the pattern of bradycardia. We conclude that nitric oxide (NO)-ergic mechanisms are involved in provoking electrical instability of the heart in conditions of endotoxemia.