RESUMO
Opioid systems in hippocampus regulate excitability and kappa opioids have a role in anticonvulsant protection, but their mechanisms of action are incompletely understood. We examined the ability of opioid and nonopioid agents with overlapping ionic mechanisms and actions similar to kappa opioid agonists, to block seizures in rat models of encephalitis due to Borna Disease virus and Herpes Simplex Virus Type-1. Naltrindole, a delta antagonist and thus a kappa opioid sparing agent, (10 mg/kg s.c.) blocked spontaneous and naloxone (opioid antagonist)-induced seizures in the models, but produced somatic signs similar to opioid withdrawal. Given that delta antagonists as well as kappa opioid agonists in hippocampus enhance potassium M currents (I(M)), we tested the effect of the I(M) augmenter flupirtine. Flupirtine (20 mg/kg i.p.) prevented seizures in Borna and herpes infected rats, without signs of withdrawal, hypotonia or sedation. The results support the efficacy of opioid and nonopioid drugs in modulating naloxone-induced seizures in critical illness due to viral encephalitis and by analogy, opioid withdrawal seizures.
Assuntos
Aminopiridinas/farmacologia , Analgésicos/farmacologia , Anticonvulsivantes/farmacologia , Encefalite Viral/tratamento farmacológico , Naltrexona/análogos & derivados , Antagonistas de Entorpecentes/farmacologia , Animais , Doença de Borna/tratamento farmacológico , Encefalite Viral/fisiopatologia , Herpes Simples/tratamento farmacológico , Herpesvirus Humano 1 , Masculino , Naloxona , Naltrexona/farmacologia , Potássio/fisiologia , Ratos , Ratos Endogâmicos Lew , Receptores Opioides delta/antagonistas & inibidores , Convulsões/induzido quimicamente , Convulsões/prevenção & controle , Síndrome de Abstinência a Substâncias/etiologia , Síndrome de Abstinência a Substâncias/prevenção & controleRESUMO
Epilepsy remains a major medical problem of unknown aetiology. Potentially, viruses can be environmental triggers for development of seizures in genetically vulnerable individuals. An estimated half of encephalitis patients experience seizures and approximately 4% develop status epilepticus. Epilepsy vulnerability has been associated with a dynorphin promoter region polymorphism or low dynorphin expression genotype, in man. In animals, the dynorphin system in the hippocampus is known to regulate excitability. The present study was designed to test the hypothesis that reduced dynorphin expression in the dentate gyrus of hippocampus due to periadolescent virus exposure leads to epileptic responses. Encephalitis produced by the neurotropic Borna disease virus in the rat caused epileptic responses and dynorphin to disappear via dentate granule cell loss, failed neurogenesis and poor survival of new neurons. Kappa opioid (dynorphin) agonists prevented the behavioural and electroencephalographic seizures produced by convulsant compounds, and these effects were associated with an absence of dynorphin from the dentate gyrus granule cell layer and upregulation of enkephalin in CA1 interneurons, thus reproducing a neurochemical marker of epilepsy, namely low dynorphin tone. A key role for kappa opioids in anticonvulsant protection provides a framework for exploration of viral and other insults that increase seizure vulnerability and may provide insights into potential interventions for treatment of epilepsy.
Assuntos
Doença de Borna/complicações , Dinorfinas/fisiologia , Encefalite Viral/complicações , Convulsões/virologia , (trans)-Isômero de 3,4-dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclo-hexil)-benzenoacetamida/uso terapêutico , Animais , Northern Blotting , Doença de Borna/metabolismo , Doença de Borna/patologia , Sobrevivência Celular , Modelos Animais de Doenças , Dinorfinas/metabolismo , Eletroencefalografia , Encefalite Viral/metabolismo , Encefalite Viral/patologia , Encefalinas/metabolismo , Hipocampo/metabolismo , Masculino , Naloxona , Antagonistas de Entorpecentes , Neurônios/patologia , Ratos , Ratos Endogâmicos Lew , Receptores Opioides kappa/agonistas , Convulsões/induzido quimicamente , Convulsões/metabolismo , Convulsões/prevenção & controleRESUMO
We determined the effects of chronic exposure to intermittent hypoxia (CIH) on chemoreflex control of ventilation in conscious animals. Adult male Sprague-Dawley rats were exposed to CIH [nadir oxygen saturation (SpO2), 75%; 15 events/h; 10 h/day] or normoxia (NORM) for 21 days. We assessed the following responses to acute, graded hypoxia before and after exposures: ventilation (VÌe, via barometric plethysmography), VÌo2 and VÌco2 (analysis of expired air), heart rate (HR), and SpO2 (pulse oximetry via neck collar). We quantified hypoxia-induced chemoreceptor sensitivity by calculating the stimulus-response relationship between SpO2 and the ventilatory equivalent for VÌco2 (linear regression). An additional aim was to determine whether CIH causes proliferation of carotid body glomus cells (using bromodeoxyuridine). CIH exposure increased the slope of the VÌe/VÌco2/SpO2 relationship and caused hyperventilation in normoxia. Bromodeoxyuridine staining was comparable in CIH and NORM. Thus our CIH paradigm augmented hypoxic chemosensitivity without causing glomus cell proliferation.
Assuntos
Hipóxia/metabolismo , Hipóxia/fisiopatologia , Animais , Dióxido de Carbono/metabolismo , Corpo Carotídeo/metabolismo , Corpo Carotídeo/fisiopatologia , Proliferação de Células/fisiologia , Células Quimiorreceptoras/metabolismo , Células Quimiorreceptoras/fisiologia , Frequência Cardíaca/fisiologia , Masculino , Oxigênio/metabolismo , Ratos , Ratos Sprague-Dawley , Respiração , Ventilação/métodosRESUMO
We evaluated several methods for characterizing hypoxic chemosensitivity in the conscious rat. Adult Sprague-Dawley rats (n = 30) were exposed to normobaric hypoxia [inspired oxygen fraction (Fio2) 0.15, 0.12, and 0.09]. We measured ventilation (VÌe; barometric plethysmography), arterial oxygen saturation (SpO2; pulse oximeter), and oxygen consumption and carbon dioxide production (VÌo2 and VÌco2; analysis of expired air). Linear regression analysis was used to define stimulus-response relationships. Testing was performed on 2 days to assess day-to-day reproducibility. Exposure to graded, steady-state hypoxia caused progressive reductions in SpO2 that were, for any given Fio2, quite variable (SpO2 range, 20-30%) among individuals. Hypoxia produced progressive increases in VÌe caused by increases in both tidal volume (VT) and breathing frequency. Hypoxia also increased the VT:inspiratory time (Ti) ratio, an indicator of central respiratory "drive." Hypoxia caused consistent, progressive declines in VÌo2, VÌco2, and core temperature (>20% at the lowest SpO2). We propose that optimal quantification of carotid chemoreceptor hypoxic sensitivity in the unanesthetized rodent should employ SpO2 [a surrogate for arterial Po2 (PaO2 )] as the stimulus variable and the ventilatory equivalent for VÌco2 (VÌe/VÌco2) and/or mean inspiratory flow rate (VT/Ti) normalized for VÌco2 as the response variables. Both metrics take into account not only the important influence of a falling metabolic rate, but also SpO2, which represents the hypoxic stimulus at the carotid body. Because of the somewhat curvilinear nature of these responses, exposure to multiple levels of graded hypoxia provides the most complete characterization of hypoxic chemosensitivity.
Assuntos
Hipóxia/fisiopatologia , Consumo de Oxigênio/fisiologia , Respiração , Animais , Pressão Arterial/fisiologia , Masculino , Pletismografia , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Taxa Respiratória/fisiologia , Volume de Ventilação Pulmonar/fisiologiaRESUMO
Up to 89% of patients with herpes simplex virus type-1 (HSV-1) encephalitis can have seizures. Possibly, viruses are environmental triggers for seizures in genetically vulnerable individuals. Inherited dynorphin promoter polymorphisms are associated with temporal lobe epilepsy and febrile seizures in man. In animals, the dynorphin system in the hippocampus regulates excitability. The hypothesis that reduced dynorphin expression in dentate gyrus of hippocampus due to HSV-1 infection leads to epileptic responses was tested in a rat model of HSV-1 encephalitis using EEG recording, histopathological and neuropharmacologic probes. HSV-1 infection causes loss of dynorphin A-like immunoreactivity in hippocampus, an effect independent of direct viral interference and cell loss. A kappa opioid receptor agonist U50488 effectively blocks ictal activity, linking absence of dynorphin to propensity for epileptic activity. These findings show a vulnerability of hippocampal dynorphin during infection, suggesting a neurochemical basis for seizures that may be generalizable to other encephalitic viruses.
Assuntos
Dinorfinas/deficiência , Encefalite por Herpes Simples/complicações , Epilepsia/metabolismo , Epilepsia/virologia , Predisposição Genética para Doença/genética , Herpesvirus Humano 1/metabolismo , Potenciais de Ação/fisiologia , Analgésicos Opioides/farmacologia , Animais , Giro Denteado/metabolismo , Giro Denteado/fisiopatologia , Giro Denteado/virologia , Modelos Animais de Doenças , Regulação para Baixo/genética , Dinorfinas/genética , Eletroencefalografia , Epilepsia/fisiopatologia , Masculino , Ratos , Ratos Endogâmicos Lew , Receptores Opioides kappa/efeitos dos fármacos , Receptores Opioides kappa/metabolismo , Fatores de RiscoRESUMO
Dyskinesias and seizures are both medically refractory disorders for which cannabinoid-based treatments have shown early promise as primary or adjunctive therapy. Using the Borna disease (BD) virus rat, an animal model of viral encephalopathy with spontaneous hyperkinetic movements and seizure susceptibility, we identified a key role for endocannabinoids in the maintenance of a balanced tone of activity in extrapyramidal and limbic circuits. BD rats showed significant elevations of the endocannabinoid anandamide in subthalamic nucleus, a relay nucleus compromised in hyperkinetic disorders. While direct and indirect cannabinoid agonists had limited motor effects in BD rats, abrupt reductions of endocannabinoid tone by the CB1 antagonist SR141716A (0.3 mg/kg, i.p.) caused seizures characterized by myoclonic jerks time-locked to periodic spike/sharp wave discharges on hippocampal electroencephalography. The general opiate antagonist naloxone (NLX) (1 mg/kg, s.c.), another pharmacologic treatment with potential efficacy in dyskinesias or L-DOPA motor complications, produced similar seizures. No changes in anandamide levels in hippocampus and amygdala were found in convulsing NLX-treated BD rats. In contrast, NLX significantly increased anandamide levels in the same areas of normal uninfected animals, possibly protecting against seizures. Pretreatment with the anandamide transport blocker AM404 (20 mg/kg, i.p.) prevented NLX-induced seizures. These findings are consistent with an anticonvulsant role for endocannabinoids, counteracting aberrant firing produced by convulsive agents, and with a functional or reciprocal relation between opioid and cannabinoid tone with respect to limbic convulsive phenomena.