RESUMO
Extracellular field potential and intracellular recordings from neurons in rat hippocampus show that, even with synaptic transmission blocked, antidromic electrical stimuli can trigger afterdischarges of up to 9 seconds duration; during these discharges action potentials of a single neuron were synchronized with extracellularly recorded population spikes. Apparently mechanisms other than recurrent chemical synapses can synchronize and recruit epileptiform events. Measurements of transmembrane potential indicate that transient extracellular electrical fields (ephaptic interactions) contribute to the observed synchrony; electrotonic coupling and changes in the concentration of extracellular ions may also contribute.
Assuntos
Hipocampo/fisiologia , Neurônios/fisiologia , Potenciais de Ação/efeitos dos fármacos , Animais , Cálcio/farmacologia , Condutividade Elétrica , Estimulação Elétrica , Potenciais Evocados/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Técnicas In Vitro , Manganês/farmacologia , Potenciais da Membrana/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Ratos , Sinapses/fisiologiaRESUMO
Alpha2-delta (alpha2-delta) is a membrane-spanning auxiliary protein subunit of voltage-gated calcium channels found in muscle and brain. Of the four subtypes of alpha2-delta, only alpha2-delta types 1 and 2 (alpha2-delta-1 and alpha2-delta-2) bind the drugs gabapentin (Neurontin) and pregabalin (Lyrica). Although recent findings indicate that drug binding to alpha2-delta-1 is required for pharmacology of pregabalin and gabapentin, previous work has not addressed the location of alpha2-delta-1 protein within nervous tissues. A monoclonal antibody to alpha2-delta-1 revealed intense immunostaining in certain areas of rat brain, spinal cord, dorsal root ganglia, and skeletal muscle, with weaker staining in heart muscle, gut and liver. Little immunostaining was seen in spleen, kidney, thymus and lung. Staining was dense in some regions of the CNS including spinal dorsal horn, anterior olfactory nucleus, anterior amygdala, basolateral (ventral) amygdala and cortical amygdala, and the piriform, perirhinal, insular and entorhinal cortices. In hippocampus, staining was heterogeneous with greater density in areas of glutamate terminals (mossy fiber endings on CA3 pyramidal cells and perforant path endings on granule cells and CA1 stratum radiatum). Moderate staining occurred in the lateral posterior nucleus of the thalamus, superficial layers of neocortex, periaqueductal gray, substantia nigra, stria terminalis, nucleus accumbens shell and tegmental nucleus. We propose that areas of dense alpha2-delta-1 staining in brain and spinal cord are likely sites of action for the analgesic, anticonvulsant and anxiolytic-like actions of pregabalin and gabapentin in animal models.
Assuntos
Encéfalo/metabolismo , Canais de Cálcio/metabolismo , Músculo Esquelético/metabolismo , Células Receptoras Sensoriais/metabolismo , Medula Espinal/metabolismo , Animais , Western Blotting , Encéfalo/anatomia & histologia , Encéfalo/citologia , Células COS , Canais de Cálcio Tipo L , Chlorocebus aethiops , Humanos , Imuno-Histoquímica , Músculo Esquelético/citologia , Ratos , Proteínas Recombinantes/metabolismo , Células Receptoras Sensoriais/citologia , Medula Espinal/anatomia & histologia , Medula Espinal/citologia , SuínosRESUMO
Textbook accounts give the impression that Na+ channels are short-acting binary switches: depolarization opens them, but only for about one millisecond. In contrast to this simplified view, a small but significant fraction of the total Na+ current in neurons occurs because channels open after long delays or in long-duration bursts of openings. Such non-inactivating Na+ current acts physiologically in neurons to amplify synaptic potentials and enhance endogenous rhythmicity, and also to aid repetitive firing of action potentials. In glial cells it also may regulate Na(+)-K+ ATPase activity. The evidence for non-inactivating Na+ current in a variety of neurons and glia is reviewed, along with a brief discussion of its ion channel substrate and its relevance for neurological diseases and drug therapy.
Assuntos
Neurônios/fisiologia , Canais de Sódio/fisiologia , Animais , Humanos , Neurônios/efeitos dos fármacos , Canais de Sódio/efeitos dos fármacosRESUMO
A simple method is presented for calculating the parameters of the hole model for distorted octahedral, low spin (t2g)5 complexes. In the case of negligible covalent bonding explicit formulas for the coefficients of the Kramer's doublet, (formula: see text). The two numerically largest g values define the plane and orientation of the orbital with the largest coefficient, which in turn indicates the directions of maximal unpaired spin density. The energy of eta with respect to xi (in units of lambda, the spin-orbit coupling constant) is (formula: see text). The product gzgygx, independent of axes, and positive for free electrons, is shown to be positive for tetragonal and negative for nearly octahedral complexes. It is considered positive for hemes. In this method coefficients will only be normalized when there is no covalency. For the majority of published cases they are, to about 1%. Since this discrepancy is larger than can be caused by propagated errors, covalency must be the rule. For comparative purposes A and B, uncorrected for covalency, should still be useful. Examination of published complete g tensors for five hemes shows that the largest g value is nearly normal to the heme plane. If the g values are taken positive and labelled so that gz greater than gy greater than gx, then the proper tetragonal axis is roughly normal to plane of the ring in hemes, but not in chlorins.
Assuntos
Heme , Cianetos , Citocromos , Espectroscopia de Ressonância de Spin Eletrônica , Ferricianetos , Ligantes , Matemática , Métodos , Conformação ProteicaRESUMO
Drugs that block voltage-dependent Na+ channels are well known as local anaesthetics, antiarrhythmics and anticonvulsants. Recent studies show that these compounds also provide a powerful mechanism of cytoprotection in animal models of cerebral ischaemia, hypoxia or head trauma. In this article Charles Taylor and Brian Meldrum review evidence indicating that Na+ channel modulators are neuroprotective and describe recent ideas for the molecular sites of action of voltage-dependent Na+ channel blockers. Clinical trials with several compounds are now in progress for stroke and traumatic head injury, and the therapeutic potential for this group of compounds is discussed.
Assuntos
Fármacos Neuroprotetores/farmacologia , Canais de Sódio/efeitos dos fármacos , Animais , Lesões Encefálicas/tratamento farmacológico , Transtornos Cerebrovasculares/tratamento farmacológico , Humanos , Fármacos Neuroprotetores/uso terapêuticoRESUMO
Significant advances have been made in understanding the molecular and cellular mechanisms underlying seizure disorders and the actions of antiepileptic drugs. Agents with new mechanisms of action or enhanced activity via known mechanisms might provide improved seizure control or more selective therapy for specific epilepsies. Gabapentin is a new antiepileptic drug that is structurally similar to the neurotransmitter GABA and the endogenous amino acid L-leucine. The mechanism of action of gabapentin is not fully understood, but its distinct profile of anticonvulsant activity in animal seizure models and its lack of activity at many drug binding sites associated with other antiepileptic drugs indicate that its mechanism of action is novel.
Assuntos
Acetatos/farmacologia , Aminas , Anticonvulsivantes/farmacologia , Ácidos Cicloexanocarboxílicos , Ácido gama-Aminobutírico , Aminoácidos/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Gabapentina , Humanos , Canais Iônicos/efeitos dos fármacos , Leucina/química , Neurotransmissores/metabolismo , Receptores de Neurotransmissores/efeitos dos fármacosRESUMO
Neocortical cultures were deprived of oxygen and glucose to model ischemic neuronal injury. We used a graded series of periods of oxygen and glucose deprivation, providing graded insults. Cell death was measured by release of lactate dehydrogenase (LDH). One hundred and twenty to 240 min of deprivation caused graded increases in glutamate overflow, LDH release and 45Ca influx. Curves of LDH release with respect to deprivation time were shifted to longer intervals by treatment with tetrodotoxin (TTX; 3, 30 or 300 nM), phenytoin (10, 30 or 100 microM), lidocaine (10, 30 or 100 microM) or the N-methyl-D-aspartate antagonist CPP [3(2-carboxypiperazine-4-yl)propyl-1-phosphonic acid, 3, 10, 30 or 100 microM]. Combined treatment with TTX and CPP caused pronounced rightward shifts of LDH deprivation curves. Our results indicate that Na+ channel blockade is neuroprotective in neocortex cultures. Our results also suggest that neuroprotection with Na+ channel blockers may be due to inhibition of glutamate release.
Assuntos
Córtex Cerebral/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Bloqueadores dos Canais de Sódio , Animais , Cálcio/metabolismo , Morte Celular/efeitos dos fármacos , Hipóxia Celular , Células Cultivadas , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Glucose/deficiência , L-Lactato Desidrogenase/metabolismo , Lidocaína/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/patologia , Fenitoína/farmacologia , Piperazinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Tetrodotoxina/farmacologiaRESUMO
The anticonvulsant effect of a series of 6-alkyl-N,N-disubstituted-2-pyridinamines is described. An investigation was carried out to optimize the anticonvulsant activity and reduce behavioral side effects in this series. Three compounds (7, 8, 10; Table I) were selected from initial screening for a more complete pharmacological evaluation. While each of these compounds was a potent anticonvulsant agent with ED50 values from 5 to 10 mg/kg, the activity was accompanied by significant behavioral side effects including decreased spontaneous locomotion, ataxia, and ptosis.
Assuntos
Aminopiridinas/uso terapêutico , Convulsões/tratamento farmacológico , Aminopiridinas/síntese química , Aminopiridinas/toxicidade , Animais , Ataxia/induzido quimicamente , Blefaroptose/induzido quimicamente , Fenômenos Químicos , Química , Eletrochoque , Excitação Neurológica , Masculino , Camundongos , Estrutura Molecular , Atividade Motora/efeitos dos fármacos , Ratos , Relação Estrutura-AtividadeRESUMO
The anticonvulsant activity of a series of 3-phenoxypyridine 1-oxides is described. An investigation carried out to optimize the activity/side effect ratio provided 4-methyl-3-phenoxypyridine 1-oxide, 3, as the derivative of choice. Overall, 3 has a pharmacological profile that is very similar to phenytoin. It exhibited significant anticonvulsant activity at doses that did not produce ataxia or sedation but caused increased spontaneous behavioral activity not seen with most anticonvulsants. The short duration of pharmacological effect of 3 was attributed to metabolic hydroxylation at the C-4 pyridine methyl group; however, structural modifications designed to inhibit this metabolic pathway were unsuccessful.
Assuntos
Anticonvulsivantes/síntese química , Óxidos N-Cíclicos/síntese química , Piridinas/síntese química , Animais , Anticonvulsivantes/farmacologia , Condicionamento Operante/efeitos dos fármacos , Óxidos N-Cíclicos/farmacologia , Hidroxilação , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Piridinas/farmacologia , Relação Estrutura-Atividade , Fatores de TempoRESUMO
A series of N-phenyl-N'-pyridinylureas was examined for anticonvulsant activity. Extensive structure/activity investigations revealed optimal activity in the N-(2,6-disubstituted-phenyl)-N'-(4-pyridinyl)urea series, with 37 exhibiting the best overall anticonvulsant profile. Compound 37 was effective against seizures induced by maximal electroshock but did not protect mice from clonic seizures produced by the convulsant pentylenetetrazol. The overall pharmacological profile suggests that 37 would be of therapeutic use in the treatment of generalized tonic-clonic and partial seizures. Compound 37 was selected for Phase 1 clinical trials.
Assuntos
Anticonvulsivantes/síntese química , Compostos de Fenilureia/síntese química , Administração Oral , Animais , Ataxia/induzido quimicamente , Fenômenos Químicos , Química , Relação Dose-Resposta a Droga , Camundongos , Compostos de Fenilureia/farmacologia , Relação Estrutura-AtividadeRESUMO
The anticonvulsant effect of a series of 6-alkoxy-N,N-disubstituted-2-pyridinamines is described. An investigation was carried out to optimize the activity/side-effect ratio in this series of compounds. The most desirable profile was seen with 1-[6-(2-methylpropoxy)-2-pyridinyl]piperazine, 6, and this compound was selected for a more complete pharmacological evaluation. Overall, 6 has a pharmacological profile that is very similar to that of diphenylhydantoin (phenytoin). While nearly equipotent to phenytoin, animal studies suggest a fairly short duration of action. In addition, 6 exhibited some troublesome side effects including central nervous system depression and hypothermia.
Assuntos
Anticonvulsivantes/síntese química , Animais , Anticonvulsivantes/farmacologia , Anticonvulsivantes/toxicidade , Ataxia/induzido quimicamente , Masculino , Camundongos , Ratos , Relação Estrutura-AtividadeRESUMO
The introduction of lipophilic groups onto the ring nitrogen of nipecotic acid and guvacine, two known GABA uptake inhibitors, afforded potent, orally-active anticonvulsant drugs. A series of compounds is reported which explores the structure-activity relationships (SAR) in this series. Among the areas explored: side-chain SAR (aromatic-, heterocyclic-, and tricyclic-containing side chains) and modifications to the tetrahydropyridine ring. The benzhydrol ether-containing side chains afforded the most potent compounds with several exhibiting in vitro IC50 values for GABA uptake of < 1 microM (including 5, Table I; 37, 43, Table IV; and 44, Table V). Compound 44 was selected for extensive evaluation and subsequently progressed to Phase 1 clinical trials with severe adverse effects seen after single dose administration to humans.
Assuntos
Anticonvulsivantes/síntese química , Inibidores da Captação de Neurotransmissores/síntese química , Ácidos Nicotínicos/síntese química , Ácidos Nipecóticos/síntese química , Prolina/análogos & derivados , Ácido gama-Aminobutírico/metabolismo , Administração Oral , Animais , Anticonvulsivantes/farmacologia , Compostos Benzidrílicos/síntese química , Compostos Benzidrílicos/farmacologia , Barreira Hematoencefálica , Humanos , Técnicas In Vitro , Camundongos , Inibidores da Captação de Neurotransmissores/farmacologia , Ácidos Nicotínicos/farmacologia , Ácidos Nipecóticos/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
In this article, the rationale for the design, synthesis, and biological evaluation of a series of N-type voltage-sensitive calcium channel (VSCC) blockers is described. N-Type VSCC blockers, such as ziconotide, have shown utility in several models of stroke and pain. Modification of the previously reported lead, 1a, led to several 4-(4-benzyloxylphenyl)piperidine structures with potent in vitro and in vivo activities. In this series, the most interesting compound, (S)-2-amino-1-{4-[(4-benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-p iperidin-1-yl}-4-methyl-pentan-1-one (11), blocked N-type calcium channels (IC(50) = 0.67 microM in the IMR32 assay) and was efficacious in the audiogenic DBA/2 seizure mouse model (ED(50) = 6 mg/kg, iv) as well as the antiwrithing model (ED(50) = 6 mg/kg, iv). Whole-cell voltage-clamp electrophysiology experiments demonstrated that compound 11 blocked N-type Ca(2+) channels and Na(+) channels in superior cervical ganglion neurons at similar concentrations. Compound 11, which showed superior in vivo efficacy, stands out as an interesting lead for further development of neurotherapeutic agents in this series.
Assuntos
Analgésicos não Narcóticos/síntese química , Anticonvulsivantes/síntese química , Bloqueadores dos Canais de Cálcio/síntese química , Neurônios/metabolismo , Piperidinas/síntese química , Estimulação Acústica , Analgésicos não Narcóticos/química , Analgésicos não Narcóticos/farmacocinética , Analgésicos não Narcóticos/farmacologia , Animais , Anticonvulsivantes/química , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/farmacocinética , Bloqueadores dos Canais de Cálcio/farmacologia , Linhagem Celular , Frequência Cardíaca/efeitos dos fármacos , Humanos , Técnicas In Vitro , Ativação do Canal Iônico , Masculino , Camundongos , Camundongos Endogâmicos DBA , Microssomos Hepáticos/metabolismo , Medição da Dor , Técnicas de Patch-Clamp , Piperidinas/química , Piperidinas/farmacocinética , Piperidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Convulsões/tratamento farmacológicoRESUMO
We performed experiments in vitro to observe electrophysiological events that may relate to the protective effect of decreased temperature during cerebral ischemia in vivo. Extracellular field potentials were recorded from area CA1 of rat hippocampal slices with reduced oxygen and 2.0 mM D-glucose, producing irreversible changes within c. 10 min (more slowly than with complete deprivation of oxygen and glucose but more rapidly than with hypoxia alone). At 36 degrees C, synaptic potentials rapidly disappeared, followed by a d.c. negative shift similar to spreading depression. Elevated oxygen and glucose were reapplied within 5 min of each negative shift (duration of hypoxia ranged from 15 to 21 min). Application of normal medium for up to 45 min after negative shifts did not allow synaptic potentials to recover. At 33 degrees C negative shifts from reduced oxygen were delayed and excitatory postsynaptic potentials recovered in one experiment. At 31 degrees C negative shifts were usually absent and synaptic potentials always recovered, even with > 50 min of reduced oxygen and glucose. At both 33 degrees C and 31 degrees C, excitatory postsynaptic potential amplitude oscillated one or more times, whether or not a negative shift occurred. Our results show that negative shifts and irreversible loss of synaptic activity from hypoxia in vitro are delayed or prevented by decreased temperature.
Assuntos
Glucose/farmacologia , Hipocampo/fisiologia , Hipóxia/fisiopatologia , Tratos Piramidais/fisiologia , Sinapses/fisiologia , Animais , Estimulação Elétrica , Potenciais Evocados/efeitos dos fármacos , Técnicas In Vitro , Ataque Isquêmico Transitório/fisiopatologia , Masculino , Fibras Nervosas/efeitos dos fármacos , Fibras Nervosas/fisiologia , Tratos Piramidais/efeitos dos fármacos , Ratos , Ratos Wistar , Sinapses/efeitos dos fármacos , TemperaturaRESUMO
In experiments on rats under urethane anaesthesia--in which the fimbria and hippocampal commissure had been cut previously to eliminate orthodromic inputs--the negative antidromic population spike evoked in CA3 by fimbrial stimulation was measured inside and outside 73 neurons in the stratum pyramidale. Subtraction of the extracellular from the intracellular records showed that on the average 39.2% (S.E. 1.93) of the extracellular population spikes appeared as a positive, depolarizing transmembrane potential. Similar measurements in the dendritic zone of CA3, where the extracellular antidromic population spike is positive, revealed a smaller and hyperpolarizing transmembrane potential, whereas presumed neuroglia showed no consistent transmembrane potential in either direction. Further tests demonstrated clear facilitation of individual pyramidal cell firing, synchronous with the antidromic population spike. These observations are consistent with the possibility that, owing to the unusually close packing and regular alignment of the pyramidal neurons, electrical field interactions in CA3 tend to promote synchronized mass discharges.
Assuntos
Hipocampo/fisiologia , Animais , Dendritos/fisiologia , Potenciais Evocados , Hipocampo/citologia , Potenciais da Membrana , Modelos Neurológicos , Neuroglia/fisiologia , Ratos , Ratos Endogâmicos , Tempo de Reação/fisiologia , Transmissão SinápticaRESUMO
The pathophysiology of brain ischemia and reperfusion injury involves perturbation of intraneuronal ion homeostasis. To identify relevant routes of ion flux, rat hippocampal slices were perfused with selective voltage- or ligand-gated ion channel blockers during experimental oxygen-glucose deprivation and subsequent reperfusion. Electron probe X-ray microanalysis was used to quantitate water content and concentrations of Na, K, Ca and other elements in morphological compartments (cytoplasm, mitochondria and nuclei) of individual CA1 pyramidal cell bodies. Blockade of voltage-gated channel-mediated Na+ entry with tetrodotoxin (1 microM) or lidocaine (200 microM) significantly reduced excess intraneuronal Na and Ca accumulation in all compartments and decreased respective K loss. Voltage-gated Ca2+ channel blockade with the L-type antagonist nitrendipine (10 microM) decreased Ca entry and modestly preserved CA1 cell elemental composition and water content. However, a lower concentration of nitrendipine (1 microM) and the N-, P-subtype Ca2+ channel blocker omega-conotoxin MVIIC (3 microM) were ineffective. Glutamate receptor blockade with the N-methyl-D-aspartate (NMDA) receptor-subtype antagonist 3-(2-carboxypiperazin-4-yl) propyl-1-phosphonic acid (CPP; 100 microM) or the alpha-amino-3-hydroxy-5-methyl-4-isoazole propionic acid (AMPA) receptor subtype blocker 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 10 microM/100 microM glycine) completely prevented Na and Ca accumulation and partially preserved intraneuronal K concentrations. Finally, the increase in neuronal water content normally associated with oxygen-glucose deprivation/reperfusion was prevented by Na+ channel or glutamate receptor blockade. Results of the present study demonstrate that antagonism of either postsynaptic NMDA or AMPA glutaminergic receptor subtypes provided nearly complete protection against ion and water deregulation in nerve cells subjected to experimental ischemia followed by reperfusion. This suggests activation of ionophoric glutaminergic receptors is involved in loss of neuronal osmoregulation and ion homeostasis. Na+ channel blockade also effectively diminished neuronal ion and water derangement during oxygen-glucose deprivation and reperfusion. Prevention of elevated Nai+ levels is likely to provide neuroprotection by decreasing presynaptic glutamate release and by improving cellular osmoregulation, adenosine triphosphate utilization and Ca2+ clearance. Thus, we suggest that voltage-gated tetrodotoxin-sensitive Na+ channels and glutamate-gated ionotropic NMDA or AMPA receptors are important routes of ion flux during nerve cell injury induced by oxygen-glucose deprivation/reperfusion.
Assuntos
Cálcio/metabolismo , Glucose/deficiência , Hipocampo/metabolismo , Hipóxia/metabolismo , Canais Iônicos/antagonistas & inibidores , Potássio/metabolismo , Sódio/metabolismo , Animais , Água Corporal/metabolismo , Bloqueadores dos Canais de Cálcio/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Hipocampo/citologia , Técnicas In Vitro , Masculino , Neurônios/metabolismo , Ratos , Ratos Wistar , Traumatismo por Reperfusão/metabolismo , Bloqueadores dos Canais de Sódio , Distribuição TecidualRESUMO
Recent experiments have shown that hippocampal pyramidal cells can generate synchronized action potentials even when chemical synapses are blocked. The computer simulations reported here showed that communication between cells by extracellular currents could cause this synchrony, provided that (1) individual neurons were sufficiently excitable and that (2) the resistivity of the extracellular medium was sufficiently high. Synchronization was enhanced if electronic junctions were also present.
Assuntos
Hipocampo/fisiologia , Potenciais de Ação , Animais , Computadores , Condutividade Elétrica , Eletrofisiologia , Epilepsia/fisiopatologia , Espaço Extracelular/fisiologia , Técnicas In Vitro , Modelos Neurológicos , Ratos , Sinapses/fisiologia , Transmissão SinápticaRESUMO
Spinal cord injury (SCI) often results in abnormal pain syndromes in patients. We present a recently developed SCI mammalian model of chronic central pain in which the spinal cord is contused at T8 using the NYU impactor device (10-g rod, 2.0-mm diameter, 12.5-mm drop height), an injury which is characterized behaviorally as moderate. Recovery of locomotor function was assessed with an open field test and scored using the open field test scale (BBB scale). Somatosensory tests of paw withdrawal responses accompanied by supraspinal responses to both mechanical punctate (von Frey hairs) and nonpunctate (4 mm diameter blunt probe) as well as thermal (radiant heat) peripheral stimuli were performed. Comparisons at the level of the individual animal between precontusion and postcontusion responses indicated significant increases in reactions to low threshold punctate mechanical stimuli, non-punctate stimuli and thermal stimuli (p < 0.05). To demonstrate the validity of this model as a central pain model, gabapentin, an agent used clinically for central pain, was given i.p. at 10 or 30 mg/kg. Gabapentin treatment significantly and reversibly changed the responses, consistent with the attenuation of the abnormal sensory behavior, and the attenuated responses lasted for the duration of the drug effect (up to 6 h). These results support the use of the spinal contusion model in the study of chronic central pain after SCI.
Assuntos
Acetatos/uso terapêutico , Aminas , Analgésicos/uso terapêutico , Contusões/tratamento farmacológico , Contusões/fisiopatologia , Ácidos Cicloexanocarboxílicos , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/fisiopatologia , Ácido gama-Aminobutírico , Animais , Comportamento Animal/efeitos dos fármacos , Doença Crônica , Contusões/psicologia , Gabapentina , Temperatura Alta , Masculino , Atividade Motora , Dor/tratamento farmacológico , Dor/fisiopatologia , Medição da Dor , Limiar da Dor/efeitos dos fármacos , Estimulação Física , Ratos , Ratos Sprague-Dawley , Tempo de Reação/efeitos dos fármacos , Traumatismos da Medula Espinal/psicologia , Fatores de TempoRESUMO
We evaluated concentrations of excitatory amino acids released from slices into the superfusing solution and also evaluated extracellular field potential recordings and histological appearance of slice tissues to evaluate several sodium-channel modulating drugs as potential treatments for ischemia. The selective sodium-channel blocker tetrodotoxin (TTX, 1 microM) reduced glutamate release from deprivation of oxygen and D-glucose, while calcium-channel blockade was ineffective. Thus, during ischemia, we propose that glutamate may be released from the free cytosolic pool ('metabolic' glutamate) rather than by exocytosis. TTX (100-500 nM) and voltage-dependent sodium-channel blockers (phenytoin, 20-100 microM; lidocaine, 2-200 microM) each prevented damage to slices without blocking action potentials. The reduction of cellular depolarization and sodium loading during ischemia may explain the neuroprotective action of several sodium-channel modulating drugs in our in vitro studies and also in animal models.
Assuntos
Isquemia Encefálica/tratamento farmacológico , Ácido Glutâmico/farmacologia , Hipocampo/fisiologia , Bloqueadores dos Canais de Sódio , Tetrodotoxina/farmacologia , Animais , Eletrofisiologia , Técnicas In Vitro , Fenitoína/farmacologia , Ratos , Ratos Endogâmicos , Fatores de TempoRESUMO
Intracellular recordings were made of anatomically identified second order neurons of the ocelli of the locust (Orthoptera, Acrididae), and the graded responses of individual neurons to illumination of the 3 ocelli were compared. It was found that two anatomical types of neurons responded with hyperpolarization to illumination of one ocellus, and with depolarization to illumination of another ocellus. The depolarizing responses were abolished with picrotoxin. The 3 anatomical types of large neurons in the median ocellar nerve had responses which were physiologically distinct.