RESUMO
OBJECTIVE: Motor cortex stimulation (MCS) is a neurosurgical technique used to treat patients with refractory neuropathic pain syndromes. MCS activates the periaqueductal gray (PAG) matter, which is one of the major centers of the descending pain inhibitory system. However, the neurochemical mechanisms in the PAG that underlie the analgesic effect of MCS have not yet been described. The main goal of this study was to investigate the neurochemical mechanisms involved in the analgesic effect induced by MCS in neuropathic pain. Specifically, we investigated the release of γ-aminobutyric acid (GABA), glycine, and glutamate in the PAG and performed pharmacological antagonism experiments to validate of our findings. METHODS: Male Wistar rats with surgically induced chronic constriction of the sciatic nerve, along with sham-operated rats and naive rats, were implanted with both unilateral transdural electrodes in the motor cortex and a microdialysis guide cannula in the PAG and subjected to MCS. The MCS was delivered in single 15-minute sessions. Neurotransmitter release was evaluated in the PAG before, during, and after MCS. Quantification of the neurotransmitters GABA, glycine, and glutamate was performed using a high-performance liquid chromatography system. The mechanical nociceptive threshold was evaluated initially, on the 14th day following the surgery, and during the MCS. In another group of neuropathic rats, once the analgesic effect after MCS was confirmed by the mechanical nociceptive test, rats were microinjected with saline or a glycine antagonist (strychnine), a GABA antagonist (bicuculline), or a combination of glycine and GABA antagonists (strychnine+bicuculline) and reevaluated for the mechanical nociceptive threshold during MCS. RESULTS: MCS reversed the hyperalgesia induced by peripheral neuropathy in the rats with chronic sciatic nerve constriction and induced a significant increase in the glycine and GABA levels in the PAG in comparison with the naive and sham-treated rats. The glutamate levels remained stable under all conditions. The antagonism of glycine, GABA, and the combination of glycine and GABA reversed the MCS-induced analgesia. CONCLUSIONS: These results suggest that the neurotransmitters glycine and GABA released in the PAG may be involved in the analgesia induced by cortical stimulation in animals with neuropathic pain. Further investigation of the mechanisms involved in MCS-induced analgesia may contribute to clinical improvements for the treatment of persistent neuropathic pain syndromes.
Assuntos
Analgesia/métodos , Estimulação Encefálica Profunda , Glicina/fisiologia , Córtex Motor/fisiopatologia , Neuralgia/terapia , Substância Cinzenta Periaquedutal/fisiopatologia , Ciática/terapia , Ácido gama-Aminobutírico/fisiologia , Animais , Bicuculina/administração & dosagem , Bicuculina/toxicidade , Vias Eferentes/efeitos dos fármacos , Vias Eferentes/fisiologia , Antagonistas GABAérgicos/administração & dosagem , Antagonistas GABAérgicos/toxicidade , Ácido Glutâmico/análise , Glicina/análise , Glicina/antagonistas & inibidores , Glicina/uso terapêutico , Hiperalgesia/tratamento farmacológico , Hiperalgesia/fisiopatologia , Hiperalgesia/terapia , Masculino , Microdiálise , Microinjeções , Neuralgia/tratamento farmacológico , Neuralgia/fisiopatologia , Limiar da Dor , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Ratos , Ratos Wistar , Nervo Isquiático/lesões , Ciática/tratamento farmacológico , Ciática/fisiopatologia , Estricnina/administração & dosagem , Estricnina/toxicidade , Ácido gama-Aminobutírico/análise , Ácido gama-Aminobutírico/uso terapêuticoRESUMO
Bombesin receptor subtype-3 (BRS-3) regulates energy homeostasis, with Brs3 knockout (Brs3(-/y)) mice being hypometabolic, hypothermic, and hyperphagic and developing obesity. We now report that the reduced body temperature is more readily detected if body temperature is analyzed as a function of physical activity level and light/dark phase. Physical activity level correlated best with body temperature 4 min later. The Brs3(-/y) metabolic phenotype is not due to intrinsically impaired brown adipose tissue function or in the communication of sympathetic signals from the brain to brown adipose tissue, since Brs3(-/y) mice have intact thermogenic responses to stress, acute cold exposure, and ß3-adrenergic activation, and Brs3(-/y) mice prefer a cooler environment. Treatment with the BRS-3 agonist MK-5046 increased brown adipose tissue temperature and body temperature in wild-type but not Brs3(-/y) mice. Intrahypothalamic infusion of MK-5046 increased body temperature. These data indicate that the BRS-3 regulation of body temperature is via a central mechanism, upstream of sympathetic efferents. The reduced body temperature in Brs3(-/y) mice is due to altered regulation of energy homeostasis affecting higher center regulation of body temperature, rather than an intrinsic defect in brown adipose tissue.
Assuntos
Tecido Adiposo Marrom/metabolismo , Regulação da Temperatura Corporal , Hipotálamo/metabolismo , Neurônios/metabolismo , Receptores da Bombesina/metabolismo , Sistema Nervoso Simpático/metabolismo , Termogênese , Tecido Adiposo Marrom/citologia , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/inervação , Agonistas de Receptores Adrenérgicos beta 3/administração & dosagem , Agonistas de Receptores Adrenérgicos beta 3/farmacologia , Animais , Regulação da Temperatura Corporal/efeitos dos fármacos , Resposta ao Choque Frio/efeitos dos fármacos , Cruzamentos Genéticos , Dioxóis/administração & dosagem , Dioxóis/farmacologia , Vias Eferentes/efeitos dos fármacos , Vias Eferentes/metabolismo , Metabolismo Energético/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Imidazóis/administração & dosagem , Imidazóis/farmacologia , Infusões Intravenosas , Infusões Intraventriculares , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora , Proteínas do Tecido Nervoso/agonistas , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/efeitos dos fármacos , Pirazóis/administração & dosagem , Pirazóis/farmacologia , Receptores da Bombesina/agonistas , Receptores da Bombesina/genética , Sistema Nervoso Simpático/efeitos dos fármacos , Termogênese/efeitos dos fármacosRESUMO
Recent studies have demonstrated that magnetic stimulation (MS) can induce cellular responses such as Ca(2+) influx into the cultured neurons and glia, leading to increased intracellular phosphorylation. We have demonstrated previously that MS reduces rat neuropathic pain associated with the prevention of neuronal degeneration. Thus, we aimed to elucidate the actions of MS in relation to modulation of spinal neuron-glia and the descending inhibitory system in chronic pain. The male SD rats intrathecally implanted with catheters were subjected to sciatic nerve ligation (CCI). MS is a low power apparatus characterized by two different frequencies, 2 KHz and 83 MHz. Rats were given MS to the skin (injured sciatic nerve) for 10 min from the seventh day after CCI. The paw withdrawal latency (PWL) evoked by thermal stimuli was measured for 14 days after CCI. Immunohistochemistry for Iba-1 or GFAP was performed after 4% paraformaldehyde fixation (microscopic analysis). We employed microdialysis for measuring CSF 5-HIAA as a reflection of 5-HT release by MS stimulation. Following CCI, rats showed a decrease in PWL after CCI, and the decrease continued until the 14th day. With MS treatment, the decrease in PWL was reduced during the 10-14 day after CCI. Injection of JNK-1 inhibitors on the 14th day antagonized the analgesic effect of MS. MS also eliminated the CCI-induced decrease in GFAP immunoreactivity. Moreover, MS evoked spinal 5-HT release reflected by increase in spinal 5-HIAA level. Thus, we demonstrate that a novel magnetic stimulator used cutaneously can ameliorate chronic pain by not only preventing abnormal spinal neuron-glia interaction, but also through the activation of the supra-spinal descending inhibitory system.
Assuntos
Dor Crônica/terapia , Vias Eferentes/patologia , Magnetoterapia/métodos , Pele/fisiopatologia , Medula Espinal/patologia , Analgesia , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/imunologia , Astrócitos/patologia , Dor Crônica/fisiopatologia , Constrição Patológica , Vias Eferentes/efeitos dos fármacos , Vias Eferentes/fisiopatologia , Proteína Glial Fibrilar Ácida/metabolismo , Ácido Hidroxi-Indolacético/metabolismo , Período de Latência Psicossexual , Masculino , Naloxona/farmacologia , Ratos , Ratos Sprague-Dawley , Pele/efeitos dos fármacos , Medula Espinal/efeitos dos fármacos , Medula Espinal/fisiopatologia , Fatores de TempoRESUMO
BACKGROUND: The neurotransmitters mediating inhibitory pathways to internal anal sphincter (IAS) have not been fully characterized. Our aim was to assess the putative release of nitric oxide, purines and vasoactive intestinal peptide (VIP) from inhibitory motor neurons (MNs) and their role in the myogenic tone, resting membrane potential (RMP) of smooth muscle cells (SMC), spontaneous inhibitory junction potentials (sIJP), mechanical relaxation, and IJP induced by electrical field stimulation (EFS) or nicotine. METHODS: Rat IAS strips were studied using organ baths, microelectrodes, and immunohistochemistry. KEY RESULTS: Internal anal sphincter strips developed active myogenic tone (0.31 g), enhanced and stabilized by prostaglandin F(2α) (PGF2α). L-NNA (1 mmol L(-1)) depolarized SMC and increased tone but did not modify sIJP. In contrast, the specific P2Y(1) receptor antagonist MRS2500 (1 µmol L(-1)) did not modify the RMP or the basal tone but abolished sIJP. Electrical field stimulation and nicotine (10 µmol L(-1)) caused IAS relaxation (-45.9%VS-52.2%), partially antagonized by L-NNA (35%-45%, P ≤ 0.05) and fully abolished by MRS2500 (P ≤ 0.001). Electrical field stimulation induced a biphasic inhibitory junction potential (IJP), the initial fast component was selectively blocked by MRS2500 and the sustained slow component was blocked by L-NNA. Vasoactive intestinal peptide 6-28 (0.1 µmol L(-1)) or α-chymotrypsin (10 U mL(-1)) did not modify the RMP, sIJP, EFS-induced IJP, or relaxation. P2Y(1) receptors were immunolocalized in the circular SMC of IAS. CONCLUSIONS & INFERENCES: The effects of inhibitory MNs on rat IAS are mediated by a functional co-transmission process involving nitrergic and purinergic pathways through P2Y(1) receptors with specific and complementary roles on the control of tone, sIJP, and hyperpolarization and relaxation of IAS following stimulation of inhibitory MNs.
Assuntos
Trifosfato de Adenosina/metabolismo , Canal Anal/inervação , Canal Anal/metabolismo , Vias Eferentes/metabolismo , Inibição Neural/fisiologia , Óxido Nítrico/metabolismo , Canal Anal/efeitos dos fármacos , Animais , Vias Eferentes/efeitos dos fármacos , Eletrofisiologia , Inibidores Enzimáticos/metabolismo , Humanos , Masculino , Potenciais da Membrana/efeitos dos fármacos , Neurônios Motores/efeitos dos fármacos , Neurônios Motores/metabolismo , Relaxamento Muscular/efeitos dos fármacos , Tono Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Inibição Neural/efeitos dos fármacos , Neurotransmissores/farmacologia , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Óxido Nítrico/farmacologia , Purinas/farmacologia , Ratos , Ratos Sprague-Dawley , Peptídeo Intestinal Vasoativo/farmacologiaRESUMO
Layer 6b in neocortex is a distinct sublamina at the ventral portion of layer 6. Corticothalamic projections arise from 6b neurons, but few studies have examined the functional properties of these cells. In the present study we examined the actions of cholecystokinin (CCK) on layer 6b neocortical neurons using whole-cell patch clamp recording techniques. We found that the general CCK receptor agonist CCK8S (sulfated CCK octapeptide) strongly depolarized the neurons, and this action persisted in the presence of tetrodotoxin, suggesting a postsynaptic site of action. The excitatory actions of CCK8S were mimicked by the selective CCK(B) receptor agonist CCK4, and attenuated by the selective CCK(B) receptor antagonist L365260, indicating a role for CCK(B) receptors. Voltage-clamp recordings revealed that CCK8S produced a slow inward current associated with a decreased conductance with a reversal potential near the K(+) equilibrium potential. In addition, intracellular cesium also blocked the inward current, suggesting the involvement of a K(+) conductance, likely K(leak). Our data indicate that CCK, acting via CCK(B) receptors, produces a long-lasting excitation of layer 6b neocortical neurons, and this action may play a critical role in modulation of corticothalamic circuit activity.
Assuntos
Potenciais de Ação/fisiologia , Colecistocinina/metabolismo , Neurônios/metabolismo , Receptor de Colecistocinina B/metabolismo , Córtex Somatossensorial/metabolismo , Tálamo/metabolismo , Potenciais de Ação/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Benzodiazepinonas/farmacologia , Colecistocinina/análogos & derivados , Colecistocinina/farmacologia , Vias Eferentes/citologia , Vias Eferentes/efeitos dos fármacos , Vias Eferentes/metabolismo , Neurônios/citologia , Neurônios/efeitos dos fármacos , Técnicas de Cultura de Órgãos , Técnicas de Patch-Clamp , Fragmentos de Peptídeos/farmacologia , Compostos de Fenilureia/farmacologia , Canais de Potássio/efeitos dos fármacos , Canais de Potássio/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor de Colecistocinina B/efeitos dos fármacos , Córtex Somatossensorial/citologia , Córtex Somatossensorial/efeitos dos fármacos , Tetragastrina/farmacologia , Tálamo/citologia , Tálamo/efeitos dos fármacosRESUMO
Orexin/hypocretin neurons of the lateral hypothalamus/perifornical area project to a diverse array of brain regions and are responsive to a variety of psychostimulant drugs. It has been shown that orexin neurons are activated by systemic nicotine administration suggesting a possible orexinergic contribution to the effects of this drug on arousal and cognitive function. The basal forebrain and paraventricular nucleus of the dorsal thalamus (PVT) both receive orexin inputs and have been implicated in arousal, attention and psychostimulant drug responses. However, it is unknown whether orexin inputs to these areas are activated by psychostimulant drugs such as nicotine. Here, we infused the retrograde tract tracer cholera toxin B subunit (CTb) into either the basal forebrain or PVT of adult male rats. Seven to 10 days later, animals received an acute systemic administration of (-) nicotine hydrogen tartrate or vehicle and were euthanized 2h later. Triple-label immunohistochemistry/immunofluorescence was used to detect Fos expression in retrogradely-labeled orexin neurons. Nicotine increased Fos expression in orexin neurons projecting to both basal forebrain and PVT. The relative activation in lateral and medial banks of retrogradely-labeled orexin neurons was similar following basal forebrain CTb deposits, but was more pronounced in the medial bank following PVT deposits of CTb. Our findings suggest that orexin inputs to the basal forebrain and PVT may contribute to nicotine effects on arousal and cognition and provide further support for the existence of functional heterogeneity across the medial-lateral distribution of orexin neurons.
Assuntos
Vias Eferentes/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Núcleos da Linha Média do Tálamo/metabolismo , Neurônios/metabolismo , Nicotina/farmacologia , Animais , Toxina da Cólera/administração & dosagem , Toxina da Cólera/metabolismo , Vias Eferentes/citologia , Vias Eferentes/efeitos dos fármacos , Imunofluorescência/métodos , Globo Pálido/citologia , Globo Pálido/efeitos dos fármacos , Globo Pálido/metabolismo , Imuno-Histoquímica/métodos , Injeções Intraperitoneais , Peptídeos e Proteínas de Sinalização Intracelular/administração & dosagem , Peptídeos e Proteínas de Sinalização Intracelular/efeitos dos fármacos , Masculino , Núcleos da Linha Média do Tálamo/citologia , Núcleos da Linha Média do Tálamo/efeitos dos fármacos , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neuropeptídeos/administração & dosagem , Neuropeptídeos/metabolismo , Neurotransmissores/administração & dosagem , Neurotransmissores/metabolismo , Neurotransmissores/farmacologia , Nicotina/administração & dosagem , Orexinas , Proteínas Proto-Oncogênicas c-fos/biossíntese , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Sprague-Dawley , Substância Inominada/citologia , Substância Inominada/efeitos dos fármacos , Substância Inominada/metabolismo , Tálamo/citologia , Tálamo/efeitos dos fármacos , Tálamo/metabolismoRESUMO
Assessing foot shock sensitivity in rodents can be useful in identifying analgesic or hyperalgesic drugs, and phenotyping inbred or genetically altered mice. Furthermore, as foot shock is an integral part of several rodent behavioral models, sensitivity should also be assessed to accurately interpret behavioral measures from these models. To eliminate variability and increase the efficiency of manually scored shock sensitivity paradigms, we utilized a startle reflex system to automatically quantify responses to varying levels of foot shock. Eight inbred mouse strains were tested for reactivity to foot shock in this system, as well as inherent startle response activity to loud noise bursts. Strain rank order for shock reactivity differed from that for acoustic startle, suggesting that pathways activated in response to each differed. Analgesic doses of morphine and acetaminophen specifically reduced foot shock responses without affecting motor reflexive responses to loud noises in each strain tested. We also tested diazepam and scopolamine, which are often used to disrupt behavior in shock-related paradigms to illustrate the usefulness of this assay. Overall, these results demonstrate that our automated method is a quick and simple way to accurately assess potential foot shock sensitivity differences owing to strain, genotype or drug treatments.
Assuntos
Analgésicos/farmacologia , Eletrochoque , Medição da Dor/instrumentação , Acetaminofen/farmacologia , Estimulação Acústica , Analgésicos não Narcóticos/farmacologia , Animais , Ansiolíticos/farmacologia , Comportamento Animal/efeitos dos fármacos , Diazepam/farmacologia , Vias Eferentes/efeitos dos fármacos , Medo/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos , Antagonistas Muscarínicos/farmacologia , Vias Neurais/efeitos dos fármacos , Reflexo de Sobressalto/efeitos dos fármacos , Escopolamina/farmacologia , Especificidade da EspécieRESUMO
Clinical and laboratory studies have suggested that amphetamine treatment when paired with rehabilitation results in improved recovery of function after stroke or traumatic brain injury. In the present study, we investigated whether new anatomical pathways developed in association with improved motor function after brain damage and amphetamine treatment linked with rehabilitation. Following a unilateral sensorimotor cortex lesion in the adult rat, amphetamine (2 mg/kg) was administered in conjunction with physiotherapy sessions on postoperative days two and five. Physiotherapy was continued twice daily for the first 3 weeks after injury, and then once daily until week six. Performance on skilled forelimb reaching and ladder rung walking was used to assess motor improvement. Our results show that animals with sensorimotor cortical lesions receiving amphetamine treatment linked with rehabilitation had significant improvement in both tasks. Neuroanatomical tracing of efferent pathways from the opposite, non-damaged cortex resulted in the novel finding that amphetamine treatment linked with rehabilitation, significantly increased axonal growth in the deafferented basilar pontine nuclei. These results support the notion that pharmacological interventions paired with rehabilitation can enhance neuronal plasticity and thereby improve functional recovery after CNS injury.
Assuntos
Anfetamina/farmacologia , Lesões Encefálicas/tratamento farmacológico , Lesões Encefálicas/reabilitação , Córtex Motor/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Recuperação de Função Fisiológica/efeitos dos fármacos , Anfetamina/uso terapêutico , Animais , Axônios/efeitos dos fármacos , Axônios/fisiologia , Axônios/ultraestrutura , Biotina/análogos & derivados , Lesões Encefálicas/fisiopatologia , Estimulantes do Sistema Nervoso Central/farmacologia , Estimulantes do Sistema Nervoso Central/uso terapêutico , Dextranos , Modelos Animais de Doenças , Vias Eferentes/efeitos dos fármacos , Vias Eferentes/fisiologia , Cones de Crescimento/efeitos dos fármacos , Cones de Crescimento/fisiologia , Cones de Crescimento/ultraestrutura , Masculino , Córtex Motor/lesões , Córtex Motor/fisiopatologia , Regeneração Nervosa/efeitos dos fármacos , Regeneração Nervosa/fisiologia , Plasticidade Neuronal/fisiologia , Paresia/tratamento farmacológico , Paresia/fisiopatologia , Paresia/reabilitação , Modalidades de Fisioterapia , Tratos Piramidais/efeitos dos fármacos , Tratos Piramidais/fisiologia , Ratos , Ratos Long-Evans , Recuperação de Função Fisiológica/fisiologia , Resultado do TratamentoRESUMO
Amantadine-sulfate has been used for several decades to treat acute influenza A, Parkinson's disease (PD), and acute or chronic drug-induced dyskinesia. Several mechanisms of actions detected in vivo/in vitro including N-methyl-D-aspartate (NMDA)-receptor antagonism, blockage of potassium channels, dopamine receptor agonism, enhancement of noradrenergic release, and anticholinergic effects have been described. We used transcranial magnetic stimulation (TMS) to evaluate the effect of single doses of amantadine on human motor cortex excitability in normal subjects. Using a double-blind, placebo-controlled, crossover study design, motor thresholds, recruitment curves, cortical stimulation-induced silent period (CSP), short intracortical inhibition (ICI), intracortical facilitation (ICF), and late inhibition (L-ICI) in 14 healthy subjects were investigated after oral doses of 50 and 100 mg amantadine with single and paired pulse TMS paradigms. Spinal cord excitability was investigated by distal latencies and M-amplitudes of the abductor digiti minimi muscle. After intake of amantadine, a significant dose-dependent decrease of ICF was noticed as well as a significant increase of L-ICI as compared to placebo. The effect on ICF and L-ICI significantly correlated with amantadine serum levels. ICI was slightly increased after amantadine intake, but the effect failed to be significant. Furthermore, amantadine had no significant effects on motor thresholds, MEP recruitment curves, CSP, or peripheral excitability. In conclusion, a low dose of amantadine is sufficient in modulating human motor cortex excitability. The decrease of ICF and increase of L-ICI may reflect glutamatergic modulation or a polysynaptic interaction of glutamatergic and GABA-ergic circuits. Although amantadine has several mechanisms of action, the NMDA-receptor antagonism seems to be the most relevant effect on cortical excitability. As L-ICI can be influenced by this type of drug, it may be an interesting parameter for studies of motor learning and use-dependent plasticity.
Assuntos
Amantadina/administração & dosagem , Potencial Evocado Motor/efeitos dos fármacos , Córtex Motor/efeitos dos fármacos , Inibição Neural/efeitos dos fármacos , Vias Neurais/efeitos dos fármacos , Adulto , Antiparkinsonianos/administração & dosagem , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Vias Eferentes/efeitos dos fármacos , Vias Eferentes/fisiologia , Eletromiografia , Potencial Evocado Motor/fisiologia , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Feminino , Ácido Glutâmico/metabolismo , Humanos , Masculino , Córtex Motor/fisiologia , Músculo Esquelético/inervação , Músculo Esquelético/fisiologia , Inibição Neural/fisiologia , Vias Neurais/fisiologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Estimulação Magnética Transcraniana , Ácido gama-Aminobutírico/metabolismoRESUMO
Recruitment of movement-related muscle synergies involves the functional linking of motor cortical points. We asked how the outputs of two simultaneously stimulated motor cortical points would interact. To this end, experiments were done in ketamine-anesthetized cats. When prolonged (e.g., 500 ms) trains of intracortical microstimulation were applied in the primary motor cortex, stimulus currents as low as 10-20 microA evoked coordinated movements of the contralateral forelimb. Paw kinematics in three dimensions and the electromyographic (EMG) activity of eight muscles were simultaneously recorded. We show that the EMG outputs of two cortical points simultaneously stimulated are additive. The movements were represented as displacement vectors pointing from initial to final paw position. The displacement vectors resulting from simultaneous stimulation of two cortical points pointed in nearly the same direction as the algebraic resultant vector. Linear summation of outputs was also found when inhibition at one of the cortical points was reduced by GABAA receptor antagonists. A simple principle emerges from these results. Notwithstanding the underlying complex neuronal circuitry, motor cortex outputs combine nearly linearly in terms of movement direction and muscle activation patterns. Importantly, simultaneous activation does not change the nature of the output at each point. An additional implication is that not all possible movements need be explicitly represented in the motor cortex; a large number of different movements may be synthesized from a smaller repertoire.
Assuntos
Vias Eferentes/fisiologia , Córtex Motor/fisiologia , Neurônios Motores/fisiologia , Movimento/fisiologia , Músculo Esquelético/fisiologia , Algoritmos , Animais , Fenômenos Biomecânicos/métodos , Mapeamento Encefálico , Gatos , Vias Eferentes/efeitos dos fármacos , Estimulação Elétrica , Eletromiografia/métodos , Potencial Evocado Motor/efeitos dos fármacos , Potencial Evocado Motor/fisiologia , Membro Anterior/inervação , Membro Anterior/fisiologia , Antagonistas GABAérgicos/farmacologia , Antagonistas de Receptores de GABA-A , Modelos Lineares , Masculino , Córtex Motor/efeitos dos fármacos , Neurônios Motores/efeitos dos fármacos , Movimento/efeitos dos fármacos , Contração Muscular/fisiologia , Músculo Esquelético/inervação , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/fisiologia , Inibição Neural/efeitos dos fármacos , Inibição Neural/fisiologia , Receptores de GABA-A/metabolismo , Transmissão Sináptica/fisiologia , Ácido gama-Aminobutírico/metabolismoRESUMO
A miswiring of prefrontal efferents is generally discussed by the name of "dysconnection" as the anatomical substrate of schizophrenia. Since direct histological confirmation of this hypothesis can hardly be obtained in humans, we used an animal model of schizophrenia to trace prefrontal efferents to distal cortical fields. Mongolian gerbils were intoxicated with a single high dose of methamphetamine on postnatal day 14 and reared in isolation after weaning (day 30). Controls received a saline injection and/or were reared under enriched conditions. Upon reaching adulthood (day 90), biocytin was injected into the medial prefrontal cortex into either deep or superficial laminae. The density of passing fibres and terminal fields in the frontal, parietal and insular cortices was assessed by digital image analysis. Isolation rearing or methamphetamine treatment alone reduced the projections from lamina V/VI to the frontal and from lamina III to the insular cortex, and from both laminae to the parietal cortex. In contrast, isolation rearing of methamphetamine-intoxicated gerbils significantly increased the projections from the deep laminae to the frontal and parietal cortices, compared to isolation-reared controls, with no difference in the efferents from superficial laminae. These results are the first to demonstrate a miswiring of prefrontal efferents in response to adverse systemic influences. They might give a hint at the anatomical basis of "dysconnection" in schizophrenia.
Assuntos
Vias Eferentes/patologia , Vias Eferentes/fisiopatologia , Metanfetamina/toxicidade , Córtex Pré-Frontal/patologia , Córtex Pré-Frontal/fisiopatologia , Esquizofrenia/fisiopatologia , Isolamento Social , Animais , Estimulantes do Sistema Nervoso Central/toxicidade , Córtex Cerebral/crescimento & desenvolvimento , Córtex Cerebral/patologia , Córtex Cerebral/fisiopatologia , Modelos Animais de Doenças , Dopamina/metabolismo , Vias Eferentes/efeitos dos fármacos , Gerbillinae , Ácido Glutâmico/metabolismo , Lisina/análogos & derivados , Masculino , Modelos Neurológicos , Lobo Parietal/crescimento & desenvolvimento , Lobo Parietal/patologia , Lobo Parietal/fisiopatologia , Córtex Pré-Frontal/efeitos dos fármacos , Terminações Pré-Sinápticas/patologia , Esquizofrenia/etiologia , Transmissão Sináptica/fisiologiaRESUMO
The lateral hypothalamus is part of an efferent system that modifies pain at the spinal cord dorsal horn, but the mechanisms by which lateral hypothalamus-induced antinociception occur are not fully understood. Previous work has shown that antinociception produced from electrical stimulation of the lateral hypothalamus is mediated in part by spinally projecting 5-hydroxytryptamine (5-HT) neurons in the ventromedial medulla. To further examine the role of the lateral hypothalamus in antinociception, the cholinergic agonist carbamylcholine chloride (125 nmol) was microinjected into the lateral hypothalamus of female Sprague-Dawley rats and nociceptive responses measured on the tail-flick and foot-withdrawal tests. Intrathecal injections of the selective 5-HT1A, 5-HT1B, 5-HT3 receptor antagonists, WAY 100135, SB-224289, and tropisetron, respectively, and the non-specific antagonist methysergide, were given. Lateral hypothalamus stimulation with carbamylcholine chloride produced significant antinociception that was blocked by WAY 100135, tropisetron, and SB-224289 on both the tail-flick and foot-withdrawal tests. Methysergide was not different from controls on the tail flick test, but increased foot-withdrawal latencies compared with controls. These results suggest that the lateral hypothalamus modifies nociception in part by activating spinally projecting serotonin neurons that act at 5-HT1A, 5-HT1B, and 5-HT3 receptors in the dorsal horn.
Assuntos
Hipotálamo/fisiologia , Dor/fisiopatologia , Células do Corno Posterior/metabolismo , Receptor 5-HT1A de Serotonina/metabolismo , Receptor 5-HT1B de Serotonina/metabolismo , Receptores 5-HT3 de Serotonina/metabolismo , Animais , Carbacol/administração & dosagem , Agonistas Colinérgicos/administração & dosagem , Vias Eferentes/efeitos dos fármacos , Vias Eferentes/metabolismo , Feminino , Hipotálamo/efeitos dos fármacos , Injeções Intraventriculares , Injeções Espinhais , Microinjeções , Nociceptores/efeitos dos fármacos , Nociceptores/metabolismo , Medição da Dor , Células do Corno Posterior/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptor 5-HT1A de Serotonina/efeitos dos fármacos , Receptor 5-HT1B de Serotonina/efeitos dos fármacos , Receptores 5-HT3 de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/administração & dosagemRESUMO
Leptin, a peptide hormone normally associated with body weight homeostasis, is implicated in the generation of obesity-induced hypertension. Administration of leptin increases sympathetic nerve activity and blood pressure; however, the neural circuity involved in this pressor effect is not clearly defined. In this review we describe experiments in which pseudorabies virus was injected into the heart, kidney and the vasculature within skeletal muscle to reveal the distribution of neurones in the hypothalamus that project to these cardiovascular tissues. This distribution is compared to the well-documented distribution of leptin receptors. Finally we discuss microinjection studies designed to examine the effect of leptin, in these regions, on sympathetic nerve discharge and arterial blood pressure. Leptin injected directly into the ventromedial hypothalamus, arcuate nucleus and lateral hypothalamic area (particularly the perifornical area) increased lumbar sympathetic nerve activity. In addition, microinjection into the ventromedial hypothalamus and parvocellular paraventricular nucleus increased blood pressure. Our results demonstrate a discrete set of hypothalamic pathways that may underlie the involvement of leptin in obesity-induced hypertension.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Leptina/fisiologia , Animais , Vias Eferentes/efeitos dos fármacos , Herpesvirus Suídeo 1/fisiologia , Humanos , Hipotálamo/química , Hipotálamo/efeitos dos fármacos , Hipotálamo/virologia , Masculino , Ratos , Receptores de Superfície Celular/análise , Receptores para Leptina , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/fisiologiaRESUMO
The vagus nerve forms a neuro-anatomical link between the gastrointestinal tract and the brain. A number of gastrointestinal hormones, including cholecystokinin and ghrelin, require an intact vagal-brainstem-hypothalamic pathway to affect CNS feeding circuits. We have shown that the effects of peripheral administration of both peptide YY(3-36) (PYY(3-36)) and glucagon-like peptide-1 (GLP-1) on food intake and activation of hypothalamic arcuate feeding neurones are abolished following either bilateral sub-diaphragmatic total truncal vagotomy or brainstem-hypothalamic pathway transectioning in rodents. These findings suggest that the vagal-brainstem-hypothalamic pathway may also play a role in the effects of circulating PYY(3-36) and GLP-1 on food intake.
Assuntos
Tronco Encefálico/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Peptídeo YY/administração & dosagem , Peptídeos/administração & dosagem , Nervo Vago/efeitos dos fármacos , Animais , Tronco Encefálico/fisiologia , Denervação/métodos , Vias Eferentes/efeitos dos fármacos , Vias Eferentes/fisiologia , Hipotálamo/fisiologia , Inibição Psicológica , Peptídeos e Proteínas de Sinalização Intercelular , Masculino , Naftalenos , Oxepinas , Fragmentos de Peptídeos , Ratos , Ratos Wistar , Vagotomia/métodos , Nervo Vago/fisiologiaRESUMO
The modulation by spinal nitric oxide (NO) of descending pathways travelling through the dorsal lateral funiculus (DLF) is a mechanism proposed for the antinociceptive effects of drugs that changes the NO metabolism. In this study we confirm that a surgical incision in the mid-plantar hind paw of rats reduces the threshold to mechanical stimulation with von Frey filaments. The incisional pain was further increased in rats with ipsilateral DLF lesion. Intrathecal L-NOARG (50-300 microg), or SIN-1 (0.1-5.0 microg) reduced, while SIN-1 (10 and 20 microg) intensified the incisional pain in rats with sham or effective lesion of the DLF. Stimulation of the dorsal raphe (DRN) or anterior pretectal (APtN) nuclei with stepwise increased electrical currents (7, 14, 21, 28 and 35 microA r.m.s.) produced a current-related reduction of the incisional pain. These nuclei activate pain inhibitory pathways that descend to the spinal cord mainly through the DLF. Intrathecal SIN-1 (5 microg) reduced, SIN-1 (20 microg) decreased and L-NOARG (150 microg) did not change the EC50 for the DRN or APtN stimulation-induced reduction of incisional pain. We conclude that the antinociceptive effects of L-NOARG or low doses of SIN-1 are independent on the activity of descending pain control pathways travelling via the DLF, but the antinociceptive effect of stimulating electrically the DRN or APtN can be summated to the effect of low dose of SIN-1 or overcome by the high dose of SIN-1.
Assuntos
Analgesia , Vias Eferentes/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Molsidomina/análogos & derivados , Molsidomina/farmacologia , Doadores de Óxido Nítrico/farmacologia , Nitroarginina/farmacologia , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Vias Eferentes/fisiopatologia , Estimulação Elétrica , Inibidores Enzimáticos/administração & dosagem , Membro Posterior , Injeções Espinhais , Masculino , Mesencéfalo/efeitos dos fármacos , Mesencéfalo/fisiopatologia , Molsidomina/administração & dosagem , Doadores de Óxido Nítrico/administração & dosagem , Nitroarginina/administração & dosagem , Dor/tratamento farmacológico , Dor/prevenção & controle , Limiar da Dor/efeitos dos fármacos , Núcleos da Rafe/efeitos dos fármacos , Núcleos da Rafe/fisiopatologia , Ratos , Ratos Wistar , Medula Espinal/efeitos dos fármacos , Medula Espinal/fisiopatologia , Medula Espinal/cirurgiaRESUMO
Corticothalamic (CT) projections are approximately 10 times more numerous than thalamocortical projections, yet their function in sensory processing is poorly understood. In particular, the functional significance of the topographic precision of CT feedback is unknown. We addressed these issues in the rodent somatosensory whisker/barrel system by deflecting individual whiskers and pharmacologically enhancing activity in layer VI of single whisker-related cortical columns. Enhancement of corticothalamic activity in a cortical column facilitated whisker-evoked responses in topographically aligned thalamic barreloid neurons, while activation of an adjacent column weakly suppressed activity at the same thalamic site. Both effects were more pronounced when stimulating the preferred, or principal, whisker than for adjacent whiskers. Thus, facilitation by homologous CT feedback sharpens thalamic receptive field focus, while suppression by nonhomologous feedback diminishes it. Our findings demonstrate that somatosensory cortex can selectively regulate thalamic spatial response tuning by engaging topographically specific excitatory and inhibitory mechanisms in the thalamus.
Assuntos
Vias Aferentes/fisiologia , Vias Eferentes/fisiologia , Retroalimentação/fisiologia , Córtex Somatossensorial/fisiologia , Tálamo/fisiologia , Vibrissas/fisiologia , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Vias Aferentes/citologia , Animais , Mapeamento Encefálico , Vias Eferentes/citologia , Vias Eferentes/efeitos dos fármacos , Retroalimentação/efeitos dos fármacos , Feminino , Antagonistas GABAérgicos/farmacologia , Inibição Neural/efeitos dos fármacos , Inibição Neural/fisiologia , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Ratos , Ratos Sprague-Dawley , Córtex Somatossensorial/citologia , Córtex Somatossensorial/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Tálamo/citologia , Tato/fisiologia , Nervo Trigêmeo/fisiologiaRESUMO
It has been mentioned in the field of aromatherapy that the fragrance of grapefruit has a refreshing and exciting effect, which suggests an activation of sympathetic nerve activity. It also can be assumed that the activation of sympathetic nerve innervating the white adipose tissue (WAT) facilitates lipolysis, then results in a suppression of body weight gain. This study addressed the effect of olfactory stimulation with the scent of grapefruit oil and lemon oil on the efferent nerve activity in the sympathetic branch of the WAT of the epididymis in the anesthetized rat. The results of the experiments demonstrated that the flavor of the citron group increased sympathetic nerve activity to WAT in anaesthetized rat, which suggests an increase in lipolysis and a suppression in body weight gain.
Assuntos
Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/inervação , Citrus , Condutos Olfatórios/fisiologia , Óleos de Plantas/farmacologia , Olfato/fisiologia , Sistema Nervoso Simpático/efeitos dos fármacos , Tecido Adiposo/fisiologia , Animais , Vias Eferentes/efeitos dos fármacos , Vias Eferentes/fisiologia , Eletrofisiologia/métodos , Epididimo/efeitos dos fármacos , Epididimo/inervação , Epididimo/fisiologia , Masculino , Ratos , Ratos Wistar , Sistema Nervoso Simpático/fisiologiaRESUMO
The effect of intrathecal administration of the 5-HT(3) receptor agonist 2-methyl-5-hydroxytryptamine (2m-5HT) on jaw muscle activity evoked by mustard oil (MO) injection into the temporomandibular joint of anesthetized rats was examined. One microgram or 100 microg of 2m-5HT significantly enhanced or suppressed jaw muscle responses, respectively. Pre-administration of tropisetron, a 5-HT(3) receptor antagonist, attenuated the effect of 2m-5HT. These results indicate that activation of 5-HT(3) receptors can modulate trigeminal nociceptive responses.
Assuntos
Vias Aferentes/metabolismo , Vias Eferentes/metabolismo , Músculos da Mastigação/fisiologia , Nociceptores/metabolismo , Agonistas do Receptor de Serotonina/farmacologia , Serotonina/análogos & derivados , Articulação Temporomandibular/inervação , Núcleo Inferior Caudal do Nervo Trigêmeo/metabolismo , Vias Aferentes/citologia , Vias Aferentes/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Interações Medicamentosas/fisiologia , Vias Eferentes/citologia , Vias Eferentes/efeitos dos fármacos , Eletromiografia , Indóis/farmacologia , Masculino , Músculos da Mastigação/inervação , Contração Muscular/efeitos dos fármacos , Contração Muscular/fisiologia , Mostardeira , Neurônios Aferentes/citologia , Neurônios Aferentes/efeitos dos fármacos , Neurônios Aferentes/metabolismo , Nociceptores/citologia , Nociceptores/efeitos dos fármacos , Extratos Vegetais/farmacologia , Óleos de Plantas , Ratos , Ratos Sprague-Dawley , Serotonina/farmacologia , Antagonistas da Serotonina/farmacologia , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Articulação Temporomandibular/efeitos dos fármacos , Articulação Temporomandibular/fisiopatologia , Núcleo Inferior Caudal do Nervo Trigêmeo/citologia , Núcleo Inferior Caudal do Nervo Trigêmeo/efeitos dos fármacos , TropizetronaRESUMO
Pretreatment with N-2-chloroethyl-N-ethyl-2-bromobenzylamine (DSP-4), a neurotoxin highly selective for the locus coeruleus (LC) projections, has recently been found to increase the vulnerability of dopaminergic nerve terminals to their selective neurotoxins. In the present study, combined treatment with a selective serotonergic (5-HT-ergic) neurotoxin parachloroamphetamine (PCA) at low doses (1 or 2 mg/kg) and a low dose of DSP-4 (10 mg/kg) led to larger decreases in 5-hydroxyindoleacetic acid (5-HIAA) levels in several brain regions than with either toxin alone. A reduction in 5-hydroxytryptamine (5-HT) turnover was observed only after the combined treatment with low doses of DSP-4 and PCA. When DSP-4 (10 mg/kg) was administered 2 months before PCA (2 mg/kg), the effect of PCA on cortical 5-HT levels was augmented, as was the effect on cortical and hypothalamic 5-HIAA levels. Conclusively, after limited alterations in the LC projections, there is an enhanced sensitivity of 5-HT-ergic nerve terminals to PCA.
Assuntos
Benzilaminas/farmacologia , Locus Cerúleo/efeitos dos fármacos , Neurotoxinas/farmacologia , Terminações Pré-Sinápticas/efeitos dos fármacos , Serotoninérgicos/farmacologia , Serotonina/metabolismo , Simpatomiméticos/farmacologia , p-Cloroanfetamina/farmacologia , Animais , Cerebelo/efeitos dos fármacos , Cerebelo/metabolismo , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Denervação , Relação Dose-Resposta a Droga , Interações Medicamentosas/fisiologia , Vias Eferentes/efeitos dos fármacos , Vias Eferentes/metabolismo , Vias Eferentes/fisiopatologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Ácido Hidroxi-Indolacético/metabolismo , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Locus Cerúleo/metabolismo , Locus Cerúleo/fisiopatologia , Masculino , Terminações Pré-Sinápticas/metabolismo , Núcleos da Rafe/efeitos dos fármacos , Núcleos da Rafe/metabolismo , Núcleos da Rafe/fisiopatologia , Ratos , Ratos WistarRESUMO
This paper is the last in a series of three investigating the role of cholinergic mechanisms in the auditory system by assessing the acute effects of nicotine, an acetylcholinomimetic drug, on aggregate responses within the auditory pathway. In a single-blind procedure, auditory responses were obtained from 20 normal-hearing, non-smokers (10 male) under two conditions (nicotine, placebo). The effects of nicotine on long-latency responses of the auditory system and on electroencephalograms are described in this paper. Results indicated that transdermal administration of nicotine to non-smokers significantly affects the afferent and efferent transmission of acoustic information, as well as enhancing cortical activation. Long-latency response amplitudes and electroencephalogram activity (dominant power and frequencies) were altered by acute doses of transdermal nicotine.