RESUMEN
Sensory neuron types have been distinguished by distinct morphological and transcriptional characteristics. Excitability is the most fundamental functional feature of neurons. Mathematical models described by Hodgkin have revealed three types of neuronal excitability based on the relationship between firing frequency and applied current intensity. However, whether natural sensory neurons display different functional characteristics in terms of excitability and whether this excitability type undergoes plastic changes under pathological pain states have remained elusive. Here, by utilizing whole-cell patch clamp recordings, behavioral and pharmacological assays, we demonstrated that large dorsal root ganglion (DRG) neurons can be classified into three classes and four subclasses based on their excitability patterns, which is similar to mathematical models raised by Hodgkin. Analysis of hyperpolarization-activated cation current (Ih) revealed different magnitude of Ih in different excitability types of large DRG neurons, with higher Ih in Class 2-1 than that in Class 1, 2-2 and 3. This indicates a crucial role of Ih in the determination of excitability type of large DRG neurons. More importantly, this pattern of excitability displays plastic changes and transition under pathological pain states caused by peripheral nerve injury. This study sheds new light on the functional characteristics of large DRG neurons and extends functional classification of large DRG neurons by integration of transcriptomic and morphological characteristics.
Asunto(s)
Potenciales de Acción , Ganglios Espinales/citología , Neuralgia/fisiopatología , Neuronas Aferentes/fisiología , Animales , Células Cultivadas , Ganglios Espinales/fisiopatología , Masculino , Plasticidad Neuronal , Neuronas Aferentes/clasificación , Ratas , Ratas Sprague-DawleyRESUMEN
Cervical radiculopathic pain is a very common symptom that may occur with cervical spondylosis. Mechanical allodynia is often associated with cervical radiculopathic pain and is inadequately treated with current therapies. However, the precise mechanisms underlying cervical radiculopathic pain-associated mechanical allodynia have remained elusive. Compelling evidence from animal models suggests a role of large-diameter dorsal root ganglion neurons and plasticity of spinal circuitry attached with Aß fibers in mediating neuropathic pain. Whether cervical radiculopathic pain condition induces plastic changes of large-diameter dorsal root ganglion neurons and what mechanisms underlie these changes are yet to be known. With combination of patch-clamp recording, immunohistochemical staining, as well as behavioral surveys, we demonstrated that upon chronic compression of C7/8 dorsal root ganglions, large-diameter cervical dorsal root ganglion neurons exhibited frequent spontaneous firing together with hyperexcitability. Quantitative analysis of hyperpolarization-activated cation current ( Ih) revealed that Ih was greatly upregulated in large dorsal root ganglion neurons from cervical radiculopathic pain rats. This increased Ih was supported by the enhanced expression of hyperpolarization-activated, cyclic nucleotide-modulated channels subunit 3 in large dorsal root ganglion neurons. Blockade of Ih with selective antagonist, ZD7288 was able to eliminate the mechanical allodynia associated with cervical radiculopathic pain. This study sheds new light on the functional plasticity of a specific subset of large-diameter dorsal root ganglion neurons and reveals a novel mechanism that could underlie the mechanical allodynia associated with cervical radiculopathy.
Asunto(s)
Ganglios Espinales/citología , Ganglios Espinales/metabolismo , Neuralgia/etiología , Neuralgia/metabolismo , Neuronas/citología , Neuronas/metabolismo , Radiculopatía/etiología , Radiculopatía/metabolismo , Animales , Dolor Crónico/etiología , Dolor Crónico/metabolismo , Dolor Crónico/patología , Masculino , Potenciales de la Membrana/fisiología , Neuralgia/patología , Neuronas Aferentes/citología , Neuronas Aferentes/metabolismo , Radiculopatía/patología , Ratas , Ratas Sprague-DawleyRESUMEN
It is known that some patients with diabetic neuropathy are usually accompanied by abnormal painful sensations. Evidence has accumulated that diabetic neuropathic pain is associated with the hyperexcitability of peripheral nociceptors. Previously, we demonstrated that reduced conduction failure of polymodal nociceptive C-fibers and enhanced voltage-dependent sodium currents of small dorsal root ganglion (DRG) neurons contribute to diabetic hyperalgesia. To further investigate whether and how potassium channels are involved in the conduction failure, α-dendrotoxin (α-DTX), a selective blocker of the low-threshold sustained Kv1 channel, was chosen to examine its functional capability in modulating the conduction properties of polymodal nociceptive C-fibers and the excitability of sensory neurons. We found that α-DTX reduced the conduction failure of C-fibers from coccygeal nerve in vivo accompanied by an increased initial conduction velocity but a decreased activity-dependent slowing of conduction velocity. In addition, the number of APs evoked by step currents was significantly enhanced after the treatment with α-DTX in small-diameter sensory neurons. Further study of the mechanism indicates α-DTX-sensitive K(+) current significantly reduced and the activation of this current in peak and steady state shifted to depolarization for diabetic neurons. Expression of Kv channel subunits Kv1.2 and Kv1.6 was downregulated in both small dorsal root ganglion neurons and peripheral C-fibers. Taken together, these results suggest that α-DTX-sensitive Kv1 channels might play an important role in regulating the conduction properties of polymodal nociceptive C-fibers and firing properties of sensory neurons.
Asunto(s)
Potenciales de Acción , Neuropatías Diabéticas/metabolismo , Fibras Nerviosas Amielínicas/metabolismo , Nocicepción , Canales de Potasio de la Superfamilia Shaker/metabolismo , Animales , Células Cultivadas , Neuropatías Diabéticas/fisiopatología , Regulación hacia Abajo , Venenos Elapídicos/farmacología , Ganglios Espinales/citología , Ganglios Espinales/metabolismo , Ganglios Espinales/fisiología , Masculino , Fibras Nerviosas Amielínicas/fisiología , Neuronas/metabolismo , Neuronas/fisiología , Bloqueadores de los Canales de Potasio/farmacología , Ratas , Ratas Sprague-Dawley , Canales de Potasio de la Superfamilia Shaker/antagonistas & inhibidores , Canales de Potasio de la Superfamilia Shaker/genéticaRESUMEN
Synaptic long-term potentiation (LTP) at spinal neurons directly communicating pain-specific inputs from the periphery to the brain has been proposed to serve as a trigger for pain hypersensitivity in pathological states. Previous studies have functionally implicated the NMDA receptor-NO pathway and the downstream second messenger, cGMP, in these processes. Because cGMP can broadly influence diverse ion-channels, kinases, and phosphodiesterases, pre- as well as post-synaptically, the precise identity of cGMP targets mediating spinal LTP, their mechanisms of action, and their locus in the spinal circuitry are still unclear. Here, we found that Protein Kinase G1 (PKG-I) localized presynaptically in nociceptor terminals plays an essential role in the expression of spinal LTP. Using the Cre-lox P system, we generated nociceptor-specific knockout mice lacking PKG-I specifically in presynaptic terminals of nociceptors in the spinal cord, but not in post-synaptic neurons or elsewhere (SNS-PKG-I(-/-) mice). Patch clamp recordings showed that activity-induced LTP at identified synapses between nociceptors and spinal neurons projecting to the periaqueductal grey (PAG) was completely abolished in SNS-PKG-I(-/-) mice, although basal synaptic transmission was not affected. Analyses of synaptic failure rates and paired-pulse ratios indicated a role for presynaptic PKG-I in regulating the probability of neurotransmitter release. Inositol 1,4,5-triphosphate receptor 1 and myosin light chain kinase were recruited as key phosphorylation targets of presynaptic PKG-I in nociceptive neurons. Finally, behavioural analyses in vivo showed marked defects in SNS-PKG-I(-/-) mice in several models of activity-induced nociceptive hypersensitivity, and pharmacological studies identified a clear contribution of PKG-I expressed in spinal terminals of nociceptors. Our results thus indicate that presynaptic mechanisms involving an increase in release probability from nociceptors are operational in the expression of synaptic LTP on spinal-PAG projection neurons and that PKG-I localized in presynaptic nociceptor terminals plays an essential role in this process to regulate pain sensitivity.
Asunto(s)
Proteínas Quinasas Dependientes de GMP Cíclico/metabolismo , Potenciación a Largo Plazo , Nociceptores/metabolismo , Dolor/patología , Aminoquinolinas/farmacología , Animales , Conducta Animal , Moléculas de Adhesión Celular/genética , Moléculas de Adhesión Celular/metabolismo , Proteína Quinasa Dependiente de GMP Cíclico Tipo I , Proteínas Quinasas Dependientes de GMP Cíclico/genética , Activación Enzimática , Ganglios Espinales/metabolismo , Ganglios Espinales/patología , Eliminación de Gen , Guanilato Ciclasa/antagonistas & inhibidores , Guanilato Ciclasa/metabolismo , Receptores de Inositol 1,4,5-Trifosfato/genética , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas de Microfilamentos/genética , Proteínas de Microfilamentos/metabolismo , Fibras Nerviosas/metabolismo , Fibras Nerviosas/patología , Nociceptores/efectos de los fármacos , Nociceptores/patología , Dolor/metabolismo , Técnicas de Placa-Clamp , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Fosforilación , Transducción de Señal , Especificidad por Sustrato , Transmisión SinápticaRESUMEN
Evidence has accumulated that reactive oxygen species and inflammation play crucial roles in the development of chronic pain, including radicular low back pain. Nonsteroid anti-inflammatory drugs (NSAIDs), for example, salicylic acid, aspirin, provided analgesic effects in various types of pain. However, long-term use of these drugs causes unwanted side effects, which limits their implication. Stable nitronyl (NIT) nitroxide radicals have been extensively studied as a unique and interesting class of new antioxidants for protection against oxidative damage. The present study synthesized a novel NIT nitroxide radical with salicylic acid framework (SANR) to provide synergistic effect of both antioxidation and antiinflammation. We demonstrated for the first time that both acute and repeated SANR treatment exerted dramatic analgesic effect in radicular low back pain mimicked by chronic compression of dorsal root ganglion in rats. This analgesic potency was more potent than that produced by classical NSAIDs aspirin and traditional nitroxide radical Tempol alone. Furthermore, SANR-induced behavioral analgesia is found to be mediated, at least in partial, by a reduction of ectopic spontaneous discharges in injured DRG neurons. Therefore, the synthesized NIT nitroxide radical coupling with salicylic acid framework may represent a novel potential therapeutic candidate for treatment of chronic pain, including radicular low back pain.
Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Óxidos N-Cíclicos/uso terapéutico , Hiperalgesia/tratamiento farmacológico , Imidazoles/uso terapéutico , Dolor de la Región Lumbar/tratamiento farmacológico , Neuronas/efectos de los fármacos , Radiculopatía/tratamiento farmacológico , Ácido Salicílico/química , Animales , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Antioxidantes/farmacología , Aspirina/farmacología , Conducta Animal/efectos de los fármacos , Óxidos N-Cíclicos/química , Óxidos N-Cíclicos/farmacología , Sinergismo Farmacológico , Ganglios Espinales/patología , Hiperalgesia/etiología , Imidazoles/química , Dolor de la Región Lumbar/patología , Dolor de la Región Lumbar/psicología , Masculino , Radiculopatía/patología , Radiculopatía/psicología , Ratas , Ratas Sprague-Dawley , Marcadores de Spin , Compresión de la Médula Espinal/tratamiento farmacológico , Compresión de la Médula Espinal/patologíaRESUMEN
Mesencephalic trigeminal nucleus (Mes V) neurons represent an uncommon class of primary sensory neurons. Besides receiving somatosensory information, Mes V neurons are also involved in regulating multisensory information. The present review first describes the passive features as well as three important currents, followed by a distinct excitability classification and a description of the excitability transition of Mes V neurons. Furthermore, their resonance property, the existence of membrane oscillation and electrical coupling which may promote strong synchronization, as well as their function in controlling stretch reflex activity, are discussed.
Asunto(s)
Fenómenos Electrofisiológicos/fisiología , Mesencéfalo/fisiología , Células Receptoras Sensoriales/fisiología , Núcleos del Trigémino/fisiología , Animales , Humanos , Mesencéfalo/citología , Células Receptoras Sensoriales/citología , Núcleos del Trigémino/citologíaRESUMEN
Usually, the main axon is assumed to faithfully conduct action potentials (APs). Recent data have indicated that neural processing can occur along the axonal path. However, the patterns and mechanisms of temporal coding are not clear. In the present study, single fiber recording was used to analyze activity-dependent modulation of AP trains in the main axons of C fibers in the rabbit saphenous nerve. Trains of 5 superthreshold electrical pulses at interstimulus intervals of 20 or 50 ms were applied to the nerve trunk for 200 s. The interspike intervals (ISIs) for these trains were compared to the input interstimulus intervals. Three basic types of C fibers were observed in response to repeated stimuli: first, the ISI between the first and second AP (ISI1-2) of type 1 was longer than the interstimulus interval; second, the ISI1-2 of type 2 showed wavelike fluctuations around the interstimulus interval, and third, the ISI1-2 of type 3 exhibited shorter intervals for a long period. Furthermore, both 4-aminopyridine-sensitive potassium and hyperpolarization-activated cation currents were involved in the modulation of ISI1-2 of train pulses. These data provide new evidence that multiple modes of neural conduction can occur along the main axons of C fibers.
Asunto(s)
Potenciales de Acción/fisiología , Nervio Femoral/fisiología , Fibras Nerviosas Amielínicas/fisiología , Animales , Axones/fisiología , Estimulación Eléctrica , Electrofisiología , Femenino , Masculino , Conducción Nerviosa/fisiología , ConejosRESUMEN
Painful diabetic neuropathy is a common complication of diabetes mellitus and can affect many aspects of life and severely limit patients' daily functions. Signals of painful diabetic neuropathy are believed to originate in the peripheral nervous system. However, its peripheral mechanism of hyperalgesia has remained elusive. Numerous studies have accumulated that polymodal nociceptive C-fibres play a crucial role in the generation and conduction of pain signals and sensitization of which following injury or inflammation leads to marked hyperalgesia. Traditionally, the number of nociceptive primary afferent firings is believed to be determined at the free nerve endings, while the extended main axon of unmyelinated C-fibres only involves the reliable and faithful propagation of firing series to the central terminals. We challenged this classic view by showing that conduction of action potential can fail to occur in response to repetitive activity when they travel down the main axon of polymodal nociceptive C-fibres. Quantitative analysis of conduction failure revealed that the degree of conduction failure displays a frequency-dependent manner. Local administration of low threshold, rapidly activating potassium current blocker, α-dendrotoxin (0.5 nM) and persistent sodium current blocker, low doses of tetrodotoxin (<100 nM) on the main axon of C-fibres can reciprocally regulate the degree of conduction failure, confirming that conduction failure did occur along the main axon of polymodal nociceptive C-fibres. Following streptozotocin-induced diabetes, a subset of polymodal nociceptive C-fibres exhibited high-firing-frequency to suprathreshold mechanical stimulation, which account for about one-third of the whole population of polymodal nociceptive C-fibres tested. These high-firing-frequency polymodal nociceptive C-fibres in rats with diabetes displayed a marked reduction of conduction failure. Delivery of low concentrations of tetrodotoxin and Nav1.8 selective blocker, A-803467 on the main axon of C-fibres was found to markedly enhance the conduction failure in a dose-dependent manner in diabetic rats. Upregulated expression of sodium channel subunits Nav1.7 and Nav1.8 in both small dorsal root ganglion neurons and peripheral C-fibres as well as enhanced transient and persistent sodium current and increased excitability in small dorsal root ganglion neurons from diabetic rats might underlie the reduced conduction failure in the diabetic high-firing-frequency polymodal nociceptive C-fibres. This study shed new light on the functional capability in the pain signals processing for the main axon of polymodal nociceptive C-fibres and revealed a novel mechanism underlying diabetic hyperalgesia.
Asunto(s)
Axones/fisiología , Neuropatías Diabéticas/fisiopatología , Hiperalgesia/fisiopatología , Conducción Nerviosa/fisiología , Nociceptores/fisiología , Potenciales de Acción/fisiología , Animales , Masculino , Fibras Nerviosas/fisiología , Ratas , Ratas Sprague-DawleyRESUMEN
Postsynaptic NMDARs at spinal synapses are required for postsynaptic long-term potentiation and chronic pain. However, how presynaptic NMDARs (PreNMDARs) in spinal nociceptor terminals control presynaptic plasticity and pain hypersensitivity has remained unclear. Here we report that PreNMDARs in spinal nociceptor terminals modulate synaptic transmission in a nociceptive tone-dependent manner. PreNMDARs depresses presynaptic transmission in basal state, while paradoxically causing presynaptic potentiation upon injury. This state-dependent modulation is dependent on Ca2+ influx via PreNMDARs. Small conductance Ca2+-activated K+ (SK) channels are responsible for PreNMDARs-mediated synaptic depression. Rather, tissue inflammation induces PreNMDARs-PKG-I-dependent BDNF secretion from spinal nociceptor terminals, leading to SK channels downregulation, which in turn converts presynaptic depression to potentiation. Our findings shed light on the state-dependent characteristics of PreNMDARs in spinal nociceptor terminals on modulating nociceptive transmission and revealed a mechanism underlying state-dependent transition. Moreover, we identify PreNMDARs in spinal nociceptor terminals as key constituents of activity-dependent pain sensitization.
Asunto(s)
Dolor Crónico/fisiopatología , Nociceptores/metabolismo , Terminales Presinápticos/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animales , Factor Neurotrófico Derivado del Encéfalo/genética , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Calcio/metabolismo , Dolor Crónico/genética , Dolor Crónico/metabolismo , Proteína Quinasa Dependiente de GMP Cíclico Tipo I/genética , Proteína Quinasa Dependiente de GMP Cíclico Tipo I/metabolismo , Ganglios Espinales/citología , Ganglios Espinales/fisiología , Inflamación , Potenciación a Largo Plazo , Depresión Sináptica a Largo Plazo , Ratones , Ratones Transgénicos , Sustancia Gris Periacueductal/citología , Sustancia Gris Periacueductal/fisiología , Canales de Potasio Calcio-Activados/genética , Canales de Potasio Calcio-Activados/metabolismo , Receptores de N-Metil-D-Aspartato/genética , Transmisión SinápticaRESUMEN
Noise can play a constructive role in the detection of weak signals in various kinds of peripheral receptors and neurons. What the mechanism underlying the effect of noise is remains unclear. Here, the perforated patch-clamp technique was used on isolated cells from chronic compression of the dorsal root ganglion (DRG) model. Our data provided new insight indicating that, under conditions without external signals, noise can enhance subthreshold oscillations, which was observed in a certain type of neurons with high-frequency (20-100 Hz) intrinsic resonance from injured DRG neurons. The occurrence of subthreshold oscillation considerably decreased the threshold potential for generating repetitive firing. The above effects of noise can be abolished by blocking the persistent sodium current (I(Na, P)). Utilizing a mathematical neuron model we further simulated the effect of noise on subthreshold oscillation and firing, and also found that noise can enhance the electrical activity through autonomous stochastic resonance. Accordingly, we propose a new concept of the effects of noise on neural intrinsic activity, which suggests that noise may be an important factor for modulating the excitability of neurons and generation of chronic pain signals.
Asunto(s)
Relojes Biológicos/fisiología , Ganglios Espinales/patología , Ruido , Radiculopatía/patología , Células Receptoras Sensoriales/fisiología , Potenciales de Acción/fisiología , Animales , Células Cultivadas , Modelos Animales de Enfermedad , Estimulación Eléctrica/métodos , Matemática , Modelos Neurológicos , Técnicas de Placa-Clamp , Ratas , Ratas Sprague-Dawley , Células Receptoras Sensoriales/clasificación , Células Receptoras Sensoriales/efectos de los fármacos , Bloqueadores de los Canales de Sodio/farmacología , Tetrodotoxina/farmacologíaRESUMEN
Recent experimental and theoretical data indicate that the functional capabilities of axons with specialized structures are much more diverse than traditionally thought. However, few observations were concerned with the main axons without arborization. In the present study, electrical stimulation of the saphenous nerve at different frequencies (2, 5, 10, 20 Hz) was used to test the role of activity-dependent effects on the pattern of action potentials that propagate along individual unmyelinated fibers (C fibers) within the trunk of the saphenous nerve in rabbits. Three basic types of C fiber responses to repetitive stimulation were observed: type-1 fibers showed an entrained response without conduction failure; type-2 fibers discharged with intermittent conduction failures; while only sporadic conduction failures happened in type 3. The failure modality in type-2 and type-3 fibers is closely related to the conductive distance as well as the frequency and duration of stimuli which lead to a critical level of conduction velocity slowing. A novel fluctuation in interspike intervals was always observed immediately before the occurrence of the failures, implying that the fluctuation of conduction velocity is correlated with imminent failures. Both the 4-aminopyridine-sensitive potassium current and hyperpolarization-activated cation current were recognized to be involved in the regulation of conduction failure patterns. The results confirmed, at least in part, the existence of conduction failures in the main axon of C fibers, suggesting that axonal operations may also be determinants for adaptation phenomenon and information processing in peripheral nervous system.
Asunto(s)
Potenciales de Acción/fisiología , Axones/fisiología , Nervio Femoral/fisiología , Fibras Nerviosas Amielínicas/fisiología , Conducción Nerviosa/fisiología , Sistema Nervioso Periférico/fisiología , 4-Aminopiridina/farmacología , Potenciales de Acción/efectos de los fármacos , Animales , Axones/efectos de los fármacos , Axones/ultraestructura , Membrana Celular/efectos de los fármacos , Membrana Celular/fisiología , Relación Dosis-Respuesta a Droga , Estimulación Eléctrica , Femenino , Nervio Femoral/citología , Activación del Canal Iónico/efectos de los fármacos , Activación del Canal Iónico/fisiología , Masculino , Fibras Nerviosas Amielínicas/efectos de los fármacos , Fibras Nerviosas Amielínicas/ultraestructura , Conducción Nerviosa/efectos de los fármacos , Sistema Nervioso Periférico/citología , Bloqueadores de los Canales de Potasio/farmacología , Canales de Potasio/efectos de los fármacos , Canales de Potasio/fisiología , Conejos , Tiempo de Reacción/efectos de los fármacos , Tiempo de Reacción/fisiología , Factores de TiempoRESUMEN
It is well known that the nucleus accumbens plays an important role in drug reinforcing effect and relapse. However, the cellular neuroadaptations that take place in accumbens neurons after repeated drug exposure are still not well understood, especially for opioids. Here, we examined how nucleus accumbens neuronal excitability becomes affected in rats exposed to morphine using whole-cell patch-clamp recordings. Medium spiny neurons recorded from brain slices of repeated morphine treated rats exhibited a significant decrease in the intrinsic excitability after 3-4 days withdrawal, compared to that of neurons from saline treated animals, which was indicated by the increase of current to evoke the first spike and the decrease of spike number induced by depolarizing current steps in the morphine group. Moreover, the excitability decrease was accompanied by related membrane property changes, such as resting membrane potential hyperpolarization, input resistance, and membrane time constant decrease, inward rectification increase, and action potential duration decrease. Taken together, repeated morphine exposure and short-term withdrawal may reduce nucleus accumbens activity and output by modulating intrinsic membrane properties of its output neurons, which could be an important neuroadaptation process that mediates morphine addictive effect.
Asunto(s)
Potenciales de Acción/efectos de los fármacos , Morfina/administración & dosificación , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Síndrome de Abstinencia a Sustancias/metabolismo , Potenciales de Acción/fisiología , Animales , Masculino , Dependencia de Morfina/metabolismo , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
Previous research has demonstrated that paradoxical sleep has a key role in learning and memory, and sleep deprivation interferes with learning and memory. However, the mechanism of memory impairment induced by sleep deprivation is poorly understood. The present study investigated the effect of paradoxical sleep deprivation (PSD) on spatial learning and memory using the Morris Water Maze. Effects of PSD on CA1 pyramidal neurons in hippocampus were also examined. PSD impaired spatial learning of rats. PSD induced translocation of Bax to mitochondria and cytochrome c release into the cytoplasm, and decreased the membrane excitability of CA1 pyramidal neurons, effects which may contribute to the deficits in learning behavior. These results may partially explain the mechanism of the effect of PSD on learning. Modulating the excitability of hippocampal neurons and protecting mitochondrial function are possible targets for preventing the effects of paradoxical sleep deprivation.
Asunto(s)
Hipocampo/metabolismo , Hipocampo/fisiopatología , Aprendizaje por Laberinto/fisiología , Membranas Mitocondriales/fisiología , Proteínas Mitocondriales/metabolismo , Privación de Sueño/fisiopatología , Privación de Sueño/psicología , Sueño REM/fisiología , Animales , Western Blotting , Peso Corporal/fisiología , Citocromos c/metabolismo , Citoplasma/enzimología , Citoplasma/metabolismo , Interpretación Estadística de Datos , Electroencefalografía , Masculino , Memoria/fisiología , Tamaño de los Órganos/fisiología , Transporte de Proteínas/genética , Transporte de Proteínas/fisiología , Desempeño Psicomotor/fisiología , Células Piramidales/fisiología , Ratas , Ratas Sprague-Dawley , Proteína X Asociada a bcl-2/metabolismoRESUMEN
We compared the responsiveness of a neural firing pacemaker in different dynamic states during the process of period-adding bifurcation to excitatory and inhibitory electrical field stimulus. In the region far from the bifurcation point, with the increase of the intensity of excitatory stimulus, the firing rate increased in an approximately linear manner and no firing pattern transition was observed. While in the region near the bifurcation point, the firing rate increased markedly higher accompanied with the transition of firing pattern when the intensity of excitatory stimulus remained the same. The stimulus-response of the region near the bifurcation point shifted upward significantly compared to that of the region far from the bifurcation point. Inhibitory stimulus with the same intensity, however, decreased the firing rate slightly without the transition of firing pattern in the region near the bifurcation point. These results suggest that the responsiveness in the region near the bifurcation point is more sensitive than that in the region far from the bifurcation point, which we named "critical sensitivity", and this has directional selectivity.
Asunto(s)
Potenciales de Acción/fisiología , Relojes Biológicos/fisiología , Neuronas/fisiología , Potenciales de Acción/efectos de la radiación , Animales , Relojes Biológicos/efectos de los fármacos , Calcio/metabolismo , Quelantes/farmacología , Relación Dosis-Respuesta a Droga , Relación Dosis-Respuesta en la Radiación , Ácido Egtácico/farmacología , Estimulación Eléctrica/métodos , Femenino , Masculino , Inhibición Neural/efectos de los fármacos , Inhibición Neural/fisiología , Inhibición Neural/efectos de la radiación , Neuronas/efectos de los fármacos , Neuronas/efectos de la radiación , Dinámicas no Lineales , Ratas , Ratas Sprague-Dawley , Neuropatía Ciática/fisiopatologíaRESUMEN
Tissue injury is known to produce inflammation and pain. Synaptic potentiation between peripheral nociceptors and spinal lamina I neurons has been proposed to serve as a trigger for chronic inflammatory pain. Gastrodin is a main bioactive constituent of the traditional Chinese herbal medicine Gastrodia elata Blume, which has been widely used as an analgesic since ancient times. However, its underlying cellular mechanisms have remained elusive. The present study demonstrated for the first time that gastrodin exhibits an analgesic effect at the spinal level on spontaneous pain, mechanical and thermal pain hypersensitivity induced by peripheral inflammation, which is not dependent on opioid receptors and without tolerance. This analgesia by gastrodin is at least in part mediated by depressing spinal synaptic potentiation via blockade of acid-sensing ion channels. Further studies with miniature EPSCs and paired-pulse ratio analysis revealed the presynaptic origin of the action of gastrodin, which involves a decrease in transmitter release probability. In contrast, neither basal nociception nor basal synaptic transmission was altered. This study revealed a dramatic analgesic action of gastrodin on inflammatory pain and uncovered a novel spinal mechanism that could underlie the analgesia by gastrodin, pointing the way to a new analgesic for treating chronic inflammatory pain.
Asunto(s)
Bloqueadores del Canal Iónico Sensible al Ácido/farmacología , Analgesia/métodos , Alcoholes Bencílicos/farmacología , Dolor Crónico , Glucósidos/farmacología , Columna Vertebral/metabolismo , Potenciales Sinápticos/efectos de los fármacos , Canales Iónicos Sensibles al Ácido/metabolismo , Animales , Dolor Crónico/tratamiento farmacológico , Dolor Crónico/metabolismo , Dolor Crónico/patología , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Inflamación/patología , Ratones , Columna Vertebral/patologíaRESUMEN
Ectopic spontaneous discharges play a critical role for both initiation and maintenance of the neuropathic pain state. Gabapentin (GBP) has been shown to be effective in animal models of neuropathic pain as well as in chronic pain patients. To investigate the peripheral mechanisms of GBP, the effects of GBP on spontaneous discharges and subthreshold membrane potential oscillation (SMPO) of chronically compressed dorsal root ganglion (DRG) were examined electrophysiolocally in vitro. The rate of spontaneous discharges was transitorily enhanced when GBP was applied to the DRG. When the concentration was under 5microM, only enhanced effect was observed, while spontaneous discharges were completely suppressed when the concentration of GBP was beyond 5microM. The similar doses of GBP blocking the spontaneous discharges failed to block the propagation of impulses by electrical nerve stimulation. Furthermore, we found that the SMPO of injured DRG cells can be selectively abolished by GBP without interrupting spike propagation. The results suggest that the inhibitory effect of GBP on SMPO might be one of the membrane mechanisms of action of GBP. This may partially explain the antinociceptive action of GBP by directly suppression nociceptive afferent input to the spinal cord.
Asunto(s)
Aminas/farmacología , Analgésicos/farmacología , Ácidos Ciclohexanocarboxílicos/farmacología , Ganglios Espinales/citología , Potenciales de la Membrana/efectos de los fármacos , Neuronas/efectos de los fármacos , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Ácido gamma-Aminobutírico/farmacología , Animales , Animales Recién Nacidos , Umbral Diferencial/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Relación Dosis-Respuesta en la Radiación , Estimulación Eléctrica/métodos , Femenino , Gabapentina , Ganglios Espinales/fisiología , Técnicas In Vitro , Masculino , Compresión Nerviosa/métodos , Fibras Nerviosas/efectos de los fármacos , Fibras Nerviosas/fisiología , Fibras Nerviosas/efectos de la radiación , Inhibición Neural/efectos de los fármacos , Neuronas/fisiología , Enfermedades del Sistema Nervioso Periférico/etiología , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
Ectopic spontaneous activity originated from the injured dorsal root ganglion (DRG) neurons in rats was recorded through single dorsal root fiber. The firing patterns induced by veratridine and aconitine, inhibitors of inactivation gate of sodium channel operating on different binding sites, were compared. In the same neuron, veratridine (1.5 approximately 5.0 micromol/L) caused slow wave oscillations of interspike intervals (ISIs), while aconitine (10 approximately 200 micromol/L) caused tonic firing. Moreover, even if the background firing patterns were various and the reagent concentrations used were different, veratridine and aconitine still induced slow wave oscillations and tonic firing patterns, respectively. The results suggest that veratridine and aconitine induce different firing patterns in injured DRG neurons, which may relate to their inhibitory effects on different binding sites of the sodium channel.
Asunto(s)
Aconitina/farmacología , Ganglios Espinales/fisiopatología , Canales de Sodio/fisiología , Veratridina/farmacología , Animales , Fenómenos Electrofisiológicos/fisiología , Femenino , Ganglios Espinales/lesiones , Masculino , Neuronas/patología , Neuronas/fisiología , Ratas , Ratas Sprague-Dawley , Agonistas de los Canales de SodioRESUMEN
OBJECTIVE: To investigate the toxicity of low dose of manganese on peripheral nervous system. METHODS: With methods of the perfusion of dorsal root ganglion (DRG) in vitro and single fiber recording of the spontaneous discharges, the effect of manganese chloride (MnCl2 1, 2, 5, 10, 50, 100 micromol/L) on neurons were observed. RESULTS: MnCl2 enhanced spontaneous discharges of DRG neurons in dose-dependent manner, but failed to affect the discharges of silent fibers. Different patterns of effects were observed in study. 1 micromol/L MnCl2 persistent enhanced the spontaneous discharges. The frequency of discharges reversed after a transient excitatory effect when 5 micromol/L MnCl2 was applied. However, 50 micromol/L MnCl2 gradually decreased the frequency of discharges followed a transient excitatory effect. CONCLUSION: These results suggest that low dose of manganese enhanced the spontaneous discharges of DRG neurons. This may partially explain the mechanism of paraesthesia in slight poison of manganese.
Asunto(s)
Potenciales de Acción/efectos de los fármacos , Contaminantes Ambientales/toxicidad , Ganglios Espinales/fisiología , Manganeso/toxicidad , Neuronas/fisiología , Potenciales de Acción/fisiología , Animales , Cloruros/toxicidad , Relación Dosis-Respuesta a Droga , Electrofisiología , Femenino , Ganglios Espinales/citología , Masculino , Compuestos de Manganeso , Conducción Nerviosa/efectos de los fármacos , Neuronas/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Nervio Ciático/efectos de los fármacos , Nervio Ciático/fisiologíaRESUMEN
Cervical radiculopathy represents aberrant mechanical hypersensitivity. Primary sensory neuron's ability to sense mechanical force forms mechanotransduction. However, whether this property undergoes activity-dependent plastic changes and underlies mechanical hypersensitivity associated with cervical radiculopathic pain (CRP) is not clear. Here we show a new CRP model producing stable mechanical compression of dorsal root ganglion (DRG), which induces dramatic behavioral mechanical hypersensitivity. Amongst nociceptive DRG neurons, a mechanically sensitive neuron, isolectin B4 negative Aδ-type (IB4(-) Aδ) DRG neuron displays spontaneous activity with hyperexcitability after chronic compression of cervical DRGs. Focal mechanical stimulation on somata of IB4(-) Aδ neuron induces abnormal hypersensitivity. Upregulated HCN1 and HCN3 channels and increased Ih current on this subset of primary nociceptors underlies the spontaneous activity together with neuronal mechanical hypersensitivity, which further contributes to the behavioral mechanical hypersensitivity associated with CRP. This study sheds new light on the functional plasticity of a specific subset of nociceptive DRG neurons to mechanical stimulation and reveals a novel mechanism that could underlie the mechanical hypersensitivity associated with cervical radiculopathy.
Asunto(s)
Ganglios Espinales/metabolismo , Ganglios Espinales/fisiopatología , Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización/genética , Mecanotransducción Celular , Nociceptores/metabolismo , Radiculopatía/genética , Radiculopatía/fisiopatología , Animales , Modelos Animales de Enfermedad , Expresión Génica , Genes fos , Hiperalgesia/etiología , Potenciales de la Membrana , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Fibras Nerviosas Mielínicas/metabolismo , Neuralgia/etiología , Fosforilación , Radiculopatía/complicaciones , Radiculopatía/etiología , Ratas , Regulación hacia ArribaRESUMEN
Under anesthesia and sterile surgery, a small stainless steel rod (4 mm in length and 0.5-0.8 mm in diameter) was inserted into the L5 intervertebral foramen in the rat, developing intervertebral foramen stenosis and hence producing a chronic steady compression of the dorsal root ganglion (DRG). The hind paw on the injured side exhibited a significant reduction in the latency of foot withdrawal to noxious heat and manifested a persistent heat hyperalgesia 5-35 days after surgery. Injection of 1% carrageenan into the intervertebral foramen, presumably causing inflammation of the DRG, also produced hyperalgesia to heat on the hind paw of the injured side 5-21 days after surgery. Extracellular electrophysiological recordings from myelinated dorsal root fibers were performed in vivo. Spontaneous activity was present in 21.5% of the fibers recorded from DRG neurons injured with chronic compression in contrast to 1.98% from uninjured DRG neurons. The pattern of spontaneous activity was periodic and bursting in 75.3% of the spontaneously active fibers. These neurons had a greatly enhanced sensitivity to mechanical stimulation of the injured DRG and a prolonged after discharge. In response to TEA, topically applied to the DRG, excitatory responses were evoked in the injured, but not the uninjured, DRG neurons. Application of this experimental model may further our understanding of the neural mechanisms by which chronic compression of DRG induces low back pain and sciatica.