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1.
Neuroscience ; 167(2): 490-500, 2010 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-20167266

RESUMO

Post-synaptic density protein PSD-95 is emerging as a valid target for modulating nociception in animal studies. Based on the key role of PSD-95 in neuronal plasticity and the maintenance of pain behavior, we predicted that CN2097, a peptide-based macrocycle of nine residues that binds to the PSD-95 Discs large, Zona occludens 1 (PDZ) domains of PSD-95, would interfere with physiologic phenomena in the spinal cord related to central sensitization. Furthermore, we tested whether spinal intrathecal injection of CN2097 attenuates thermal hyperalgesia in a rat model of sciatic neuropathy. Results demonstrate that spinal CN2097 reverses hyperexcitability of wide dynamic range (WDR) neurons in the dorsal horn of neuropathic rats and decreases their evoked responses to peripheral stimuli (brush, low caliber von Frey and pressure), whereas CN5125 ("negative control") has no effect. CN2097 also blocks C-fiber long-term potentiation (LTP) in the dorsal horn, which is linked to neuronal plasticity and central sensitization. At a molecular level, CN2097 attenuates the increase in phosphorylated p38 MAPK, a key intracellular signaling pathway in neuropathic pain. Moreover, spinal injection of CN2097 blocks thermal hyperalgesia in neuropathic rats. We conclude that CN2097 is a small molecule peptide with putative anti-nociceptive effects that modulates physiologic phenomena related to central sensitization under conditions of chronic pain.


Assuntos
Analgésicos/farmacologia , Hiperalgesia/prevenção & controle , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Membrana/metabolismo , Peptídeos Cíclicos/farmacologia , Medula Espinal/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Animais , Proteína 4 Homóloga a Disks-Large , Temperatura Alta , Humanos , Hiperalgesia/fisiopatologia , Injeções Espinhais , Ligantes , Potenciação de Longa Duração/efeitos dos fármacos , Região Lombossacral , Fibras Nervosas Amielínicas/efeitos dos fármacos , Fibras Nervosas Amielínicas/fisiologia , Domínios PDZ , Dor/fisiopatologia , Dor/prevenção & controle , Doenças do Sistema Nervoso Periférico/fisiopatologia , Doenças do Sistema Nervoso Periférico/prevenção & controle , Fosforilação , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Nervo Isquiático/fisiopatologia , Medula Espinal/fisiopatologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
2.
Exp Neurol ; 210(2): 286-94, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18201702

RESUMO

Therapies aimed at depleting or blocking the migration of polymorphonuclear leukocytes (PMN or neutrophils) are partially successful in the treatment of neuroinflammatory conditions and in attenuating pain following peripheral nerve injury or subcutaneous inflammation. However, the functional effects of PMN on peripheral sensory neurons such as dorsal root ganglia (DRG) neurons are largely unknown. We hypothesized that PMN are detrimental to neuronal viability in culture and increase neuronal activity and excitability. We demonstrate that isolated peripheral PMN are initially in a relatively resting state but undergo internal oxidative burst and activation by an unknown mechanism within 10 min of co-culture with dissociated DRG cells. Co-culture for 24 h decreases neuronal count at a threshold<0.4:1 PMN:DRG cell ratio and increases the number of injured and apoptotic neurons. Within 3 min of PMN addition, fluorometric calcium imaging reveals intracellular calcium transients in small size (<25 microm diam) and large size (>25 microm diam) neurons, as well as in capsaicin-sensitive neurons. Furthermore, small size isolectin B4-labeled neurons undergo hyperexcitability manifested as decreased current threshold and increased firing frequency. Although co-culture of PMN and DRG cells does not perfectly model neuroinflammatory conditions in vivo, these findings suggest that activated PMN can potentially aggravate neuronal injury and cause functional changes to peripheral sensory neurons. Distinguishing the beneficial from the detrimental effects of PMN on neurons may aid in the development of more effective drug therapies for neurological disorders involving neuroinflammation, including painful neuropathies.


Assuntos
Gânglios Espinais/citologia , Neurônios/fisiologia , Neutrófilos/fisiologia , Anestésicos Locais/farmacologia , Animais , Anexina A5/metabolismo , Cálcio/metabolismo , Contagem de Células , Células Cultivadas , Técnicas de Cocultura/métodos , Relação Dose-Resposta à Radiação , Estimulação Elétrica/métodos , Proteína Glial Fibrilar Ácida/metabolismo , Lidocaína/farmacologia , Masculino , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Potenciais da Membrana/efeitos da radiação , Neurônios/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Técnicas de Patch-Clamp/métodos , Fosfopiruvato Hidratase/metabolismo , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Fator de Necrose Tumoral alfa/farmacologia
3.
J Neuroimmunol ; 184(1-2): 164-71, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17275921

RESUMO

To test whether neutrophils (PMN) target lumbar dorsal root ganglia (DRG) following axonal injury leading to neuropathic pain, we visualized PMN infiltration in DRG tissue sections and estimated PMN count by flow cytometry following sciatic chronic constriction injury (CCI). Seven days after CCI, results show PMN within DRG where their count increased by three fold ipsilateral to injury compared to contralateral or sham, concomitant with peak neuropathic pain behavior. Superoxide burst in PMN isolated from rats d7 after CCI was elevated by 170% +/-18 compared to naïve and MCP-1 mRNA expression in DRG increased by 8.9+/-2.9 fold, but that of MIP-2, CINC-1, and RANTES did not change. We conclude that CCI causes PMN invasion of the DRG whereby the functional implication of their close proximity to neuronal axon and soma remains unknown.


Assuntos
Gânglios Espinais/patologia , Neutrófilos/fisiologia , Neuropatia Ciática/patologia , Neuropatia Ciática/fisiopatologia , Animais , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Constrição , Lateralidade Funcional , Regulação da Expressão Gênica/fisiologia , Região Lombossacral , Masculino , Medição da Dor/métodos , RNA Mensageiro/metabolismo , Ratos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Tempo
4.
Exp Brain Res ; 146(1): 117-21, 2002 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12192585

RESUMO

The cerebellum modulates different nociceptive phenomena and influences visceral functions. This study shows cerebellar modulation of an abdominal reflex elicited by a visceral noxious stimulus (colorectal distension, CRD). The intensity of the reflex was measured by electromyographic (EMG) recording from the rectus abdominus muscle, and the cerebellar cortex (vermis, lobule VIII), the fastigial nucleus, or the dentate nucleus was stimulated using D, L-homocysteic acid (0.1 M, 1 micro l). To release the fastigial nucleus from inhibition by the Purkinje cells, bicuculline (GABA(A) receptor antagonist, 100 micro M, 1 micro l) was used. Stimulation of the cerebellar cortex enhanced, whereas stimulation or disinhibition of the fastigial nucleus decreased, the responses to CRD measured by EMG. Stimulation of the dentate nucleus did not have an obvious effect on the intensity of the reflex. These results are in agreement with the hypothesis that the cerebellum modulates visceral nociceptive functions, whereby the cerebellar cortex and the fastigial nucleus, respectively, play a pro-nociceptive and an anti-nociceptive role.


Assuntos
Cerebelo/fisiologia , Homocisteína/análogos & derivados , Nociceptores/fisiologia , Dor/fisiopatologia , Reflexo/fisiologia , Animais , Bicuculina/farmacologia , Mapeamento Encefálico , Córtex Cerebelar/fisiologia , Colo/inervação , Colo/fisiologia , Estimulação Elétrica , Eletromiografia , Agonistas GABAérgicos/farmacologia , Homocisteína/farmacologia , Masculino , Músculo Esquelético/inervação , Músculo Esquelético/fisiologia , Vias Neurais/fisiologia , Estimulação Física , Ratos , Ratos Sprague-Dawley , Reto/inervação , Reto/fisiologia , Técnicas Estereotáxicas
5.
Neurosci Lett ; 327(1): 17-20, 2002 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-12098490

RESUMO

The cerebellum was recently proposed to play a role in cognition and sensation in addition to motor phenomena. We have shown that the cerebellum is involved in the processing of sensory nociceptive information. In this study, the activity of neurons in the dorsal column nuclei (DCN) was tested following stimulation in the rat fastigial nucleus. The results showed an enhancement of the extracellularly recorded responses of DCN neurons to somatic non-noxious stimuli following injection of D,L-homocysteic acid (0.1 M, 1 microl) into the area of the fastigial nucleus. We conclude that the cerebellum influences the processing of non-noxious somatosensory information at the level of the DCN, an important relay and a center for the processing of fine tactile and vibratory information. This observation is not yet supported by clinical data.


Assuntos
Núcleos Cerebelares/citologia , Núcleos Cerebelares/fisiologia , Homocisteína/análogos & derivados , Neurônios Aferentes/fisiologia , Tato/fisiologia , Potenciais de Ação/fisiologia , Animais , Homocisteína/farmacologia , Masculino , Estimulação Física , Ratos , Ratos Sprague-Dawley , Vibração
6.
Exp Brain Res ; 140(1): 122-6, 2001 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-11500804

RESUMO

The cerebellum is a system with various input and output functions that influence motor, sensory, cognitive, and other processes. In a previous study, we showed that cerebellar cortical stimulation increases spinal neuronal responses to visceral noxious stimulation by colorectal distension (CRD). However, the neuronal network underlying the cerebellar modulation of nociceptive phenomena is largely unknown. Purkinje cells of the cerebellar cortex receive ascending and descending inputs and exert a major inhibitory control over neurons in the underlying cerebellar nuclei that constitute the cerebellar output. Therefore, in this study, we tested the effect of CRD and other somatic stimuli on the firing rate of Purkinje cells using in vivo extracellular recording techniques. The results suggest that Purkinje cells respond to nociceptive visceral and somatic stimulation in the form of early and delayed changes in activity. Based on these and previous findings, we propose a negative feedback circuitry involving the cerebellum for the modulation of peripheral nociceptive events.


Assuntos
Potenciais de Ação/fisiologia , Nociceptores/fisiologia , Dor/fisiopatologia , Células de Purkinje/fisiologia , Fibras Aferentes Viscerais/fisiologia , Vias Aferentes/fisiologia , Animais , Relógios Biológicos/fisiologia , Cateterismo/efeitos adversos , Pé/inervação , Pé/fisiologia , Mecanorreceptores/fisiologia , Estimulação Física/métodos , Células do Corno Posterior/fisiologia , Ratos , Ratos Sprague-Dawley , Tempo de Reação/fisiologia , Reto/inervação , Reto/fisiopatologia
7.
J Neurophysiol ; 85(6): 2359-63, 2001 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-11387382

RESUMO

The role of the cerebellum in modulating nociceptive phenomena is unclear. In this study, we focus on the effects of cerebellar cortical stimulation on the responses of midline neurons of the lumbosacral spinal cord to graded nonnoxious and noxious visceral (colorectal distension) as well as somatic (brush, pressure, pinch) stimuli. Extracellular recording was used for the isolation and recording of spinal nociceptive neurons, while electrical current pulses and chemical injection of D, L-homocysteic acid were used to stimulate the cortex of the posterior cerebellar vermis. Cerebellar cortical stimulation increased the responses of all isolated cells to colorectal distension, whereas the effect on the responses to somatic stimuli was variable. These findings indicate that the posterior cerebellar vermis may exert a pro-nociceptive effect on spinal visceroceptive neurons.


Assuntos
Cerebelo/fisiologia , Nociceptores/fisiologia , Medula Espinal/fisiologia , Fibras Aferentes Viscerais/fisiologia , Animais , Cateterismo , Cerebelo/citologia , Estimulação Elétrica , Eletrofisiologia , Masculino , Estimulação Física , Ratos , Ratos Sprague-Dawley , Medula Espinal/citologia
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